Palladium-Catalyzed C(sp3)?H Arylation of Primary Amines Using a Catalytic Alkyl Acetal to Form a Transient Directing Group

Article abstract of DOI:10.1002/chem.201804515

C?H Functionalization of amines is a prominent challenge due to the strong complexation of amines to transition metal catalysts, and therefore typically requires derivatization at nitrogen with a directing group. Transient directing groups (TDGs) permit C?H functionalization in a single operation, without needing these additional steps for directing group installation and removal. Here we report a palladium catalyzed γ-C?H arylation of amines using catalytic amounts of alkyl acetals as transient activators (e.g. commercially available (2,2-dimethoxyethoxy)benzene). This simple additive enables arylation of amines with a wide range of aryl iodides. Key structural features of the novel TDG are examined, demonstrating an important role for the masked carbonyl and ether functionalities. Detailed kinetic (RPKA) and mechanistic investigations determine the order in all reagents, and identify cyclopalladation as the turnover limiting step. Finally, the discovery of an unprecedented off-cycle free-amine directed ?-cyclopalladation of the arylation product is reported.

Full text of DOI:10.1002/chem.201804515

A Journal of
Accepted Article
Title: Palladium Catalyzed C(sp3)–H Arylation of Primary Amines Using
a Catalytic Alkyl Acetal to Form a Transient Directing Group
Authors: Sahra St John-Campbell, Alex K Ou, and James Adam Bull
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To be cited as: Chem. Eur. J. 10.1002/chem.201804515
Link to VoR: http://dx.doi.org/10.1002/chem.201804515
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10.1002/chem.201804515
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Palladium Catalyzed C(sp3)–H Arylation of Primary Amines Using
a Catalytic Alkyl Acetal to Form a Transient Directing Group
Sahra St John-Campbell, Alex K. Ou and James A. Bull*
a) Gaunt: Arylation of hindered amines
Abstract: C–H Functionalization of amines is a prominent challenge
Pd(OAc)2 (10 mol%)
due to the strong complexation of amines to transition metal catalysts,
and therefore typically requires derivatisation at nitrogen with a
directing group. Transient directing groups (TDG) permit C–H
BQ, Ac-Phe-OH
Ar
NH
NH
Ar
(pin)B
AgCO3, NaHCO3
t-amylOH, 80 ºC, air
b) Amine arylation with catalytic transient directing groups
functionalization in
a single operation, without needing these
Ge (2016)
ArI
additional steps for directing group installation and removal. Here we
report a palladium catalysed γ-C–H arylation of amines using catalytic
amounts of alkyl acetals as transient activators (e.g. commercially
available (2,2-dimethoxyethoxy)-benzene). This simple additive
enables arylation of amines with a wide range of aryl iodides. Key
structural features of the novel TDG are examined, demonstrating an
important role for the masked carbonyl and ether functionalities.
Detailed kinetic (RPKA) and mechanistic investigations determine the
order in all reagents, and identify cyclopalladation as the turnover
limiting step. Finally, the discovery of an unprecedented off-cycle free-
amine directed ε-cyclopalladation of the arylation product is reported.
Pd(OAc)2 (10 mol%)
DG1 (20 mol%)
DG1
H2N
H
H2N
Ar
Ar
O
O
AgTFA, H2O
AcOH
100 °C, 15 h
R
R
R R
OH
Yu (2016)
H2N
i)
ArI
DG2
R
Pd(OAc)2 (10 mol%)
DG2 (20 mol%)
R
O
H
BocHN
AgTFA, H2O
HFIP:AcOH (19:1)
120 °C, 12 h
N
OH
R
R
R
R
R
R
ii)
Boc protection
c) This work: Aliphatic acetal transient activator
OAr’
N
acetal
ArI
OMe
OMe
Pd cat (10 mol%)
acetal (15 mol%)
R
R
Ar’O
H
H2N
H
H2N
Ar
R
AgTFA, H2O
HFIP:AcOH
proposed via
imine intermediate:
R
R
R
R
R
R
Introduction
Scheme 1. Palladium catalysed C(sp3)–H arylation of unprotected amines.
Amines are crucial structural features in biological molecules,
pharmaceuticals and agrochemical products.[1] Numerous simple
aliphatic amines are commercially available and react at nitrogen
with well-established transformations. In contrast, derivatization
of amines by C–C bond formation at unactivated positions
remains a frontier challenge in synthesis. Transition metal
catalysed C(sp3)–H functionalization offers huge potential for
such value adding transformations of feedstock chemicals.[2]
However, free amine substrates deactivate metal catalysts by
strong coordination, and readily undergo oxidation by β-hydride
elimination,[3] typically preventing the desired transformation.
Important recent developments have derivatized nitrogen with
amide or sulfonamide directing groups to modify the coordinating
ability of the amine and to direct C–H functionalization.[4] This
requires additional steps for directing group installation and
removal. Very few C(sp3)–H functionalization methods have been
successful on unprotected amines. Notably, Gaunt developed
palladium catalysed functionalization of hindered secondary
amine substrates,[5] to avoid formation of inactive bis(amine)
of t-amylamine in AcOH with diacetoxyiodobenzene as the
oxidant, minimizing inactive amine-Pd complexes by
protonation.[6]
Very recently, transient directing groups (TDGs) have been
applied to the functionalization of C(sp3)–H bonds,[7] particularly
arylation of aldehyde and ketone substrates via endo-imines
formed in situ with amine additives.[8] The use of exo-imine
directing groups for C–H functionalization of primary amines
remains rare, with examples using palladium catalysis.[9-12] In
2016 Dong used stoichiometric 8-formylquinoline to form an imine
which effected arylation with bisaryliodonium salts.[9] At a similar
time, Ge reported the catalytic use of glycoxylic acid to form a
transient imine directing group for arylation of t-amylamine
derivatives
(Scheme
1b).[10]
Yu
reported
catalytic
2-hydroxynicotinaldehyde as a highly effective directing group,
compatible with propylamine as well as α- and β-branched
amines.[11] In 2017 Murakami used a stoichiometric salicaldehyde
in separate imine formation and hydrolysis steps, completed in a
1-pot sequence.[12] While preparing this manuscript, Young
reported the use of carbon dioxide to promote C–H arylation of
primary and secondary aliphatic amines.[13]
palladium
complexes,
including
the
arylation
of
tetramethylpiperidines (Scheme 1a).[5d] Shi reported acetoxylation
[a]
S. St John-Campbell, A. K. Ou, Dr J. A. Bull
Department of Chemistry
Imperial College London
Molecular Sciences Research Hub, White City Campus, Wood
Lane, W12 0BZ (UK)
E-mail: j.bull@imperial.ac.uk
Here we report new transient directing groups for C–H
functionalization of amines with the first examples of alkyl
aldehydes as transient directing groups (Scheme 1c). The use of
a stable acetal precursor in low catalytic loadings promotes the γ-
arylation of primary amines with aryl iodides using palladium
catalysis. Furthermore, we report detailed kinetic (RPKA) and
mechanistic investigations. These studies provided important
insights into the reaction, including reaction orders of all
Homepage: http://www3.imperial.ac.uk/people/j.bull
Supporting information for this article is available on the WWW
under:
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10.1002/chem.201804515
Chemistry - A European Journal
FULL PAPER
OMe
OMe
components
and
the
identification
of
an
unusual
X
ε-cyclometallation pathway of the arylated products.
TDG (0.15 equiv)
Pd(OAc)2 (5 mol%)
AgTFA (2 equiv)
H2N
H
H2N
Ph
PhI
(3 equiv)
1
AcOH (0.2 M), H2O (5 equiv)
110 °C, 18 h
2a
no additive: 26%
Results and Discussion
TDGs
OMe
OMe
OMe
OMe
OMe
OMe
H
Tol
S
N
O
F3C
O
MEMO
OMe
OMe
Me
We envisaged using alkyl aldehydes as TDGs for primary amine
C–H arylation in order to aid reversible imine formation and open
new possibilities for transient directing groups in C–H
functionalization. This would enable a second coordinating site to
be included at the α-position of the aldehyde, which could be
readily tuned to optimise the properties. The secondary
coordinating groups were intended to provide a chelate to
stabilize intermediates on the catalytic cycle,[14] limit imine
isomerization, increase aldehyde electrophilicity and prevent
cyclometalation of the directing group. However, such
functionalized aldehydes are typically unstable to storage, and
therefore we considered the use of acetals as more accessible
alternatives, being easily prepared and commercially available.
This would be the first example of this type of transient directing
group in any C–H functionalization reaction.
O
O
3 9%
4 36%
OMe
OMe
5 24%
6 41%
OMe
OMe
OMe
OMe
O
HO
O
O
O
H
MeO
7 32%
Me
8 46%
9 41%
OMe
OMe
10 36%
OMe
OMe
OMe
OMe
O
O
F3C
O
Me
11 34%
F3C
12 57%
13 29%
CF3
Scheme 2. Screen of alkyl acetals as transient directing groups for amine
arylation. Yields determined by 1H NMR using 1,3,5-trimethoxybenzene as an
internal standard
After initial investigation, a screen of different potential
TDGs was conducted using palladium acetate with silver
trifluoroacetate in acetic acid and water as solvent (Scheme 2).
Under these conditions, in the absence of any additional TDG
using t-amylamine 1, the free amine promoted the arylation in
26% yield, which we aimed to improve by invoking a transient
imine strategy. In comparison to our previous work using mono-
N-Ts ethylenediamine as a TDG for aldehyde C–H arylation,[8c]
we first considered 2-N-tosyl acetaldehyde acetal 3. Addition of
0.15 equiv of the acetal gave a decreased yield compared to the
background reaction, presumably due to strong coordination to
the palladium catalyst. However, an improved yield was achieved
by using methoxy derivative 4. Trifluoroethyl ether 5 had no
beneficial effect on the reaction. A potentially tridentate TDG
containing a MEM protected alcohol 6 improved the yield to 41%,
whereas the corresponding free alcohol 7 gave 32% yield.
Pleasingly, commercially available phenoxyacetaldehyde
dimethyl acetal 8 gave an improved 46% yield. Its corresponding
aldehyde 9 gave a similar result, consistent with hydrolysis under
the reaction conditions. We then investigated variations to the
aromatic ether. p-Methoxy substituted derivative 10 was less
effective than the phenyl ether, and the more hindered 2,6-
dimethoxy example 11 also gave a lower yield. Electron poor 4-
trifluoromethylphenyl derivative 12 gave the highest yield of 57%.
Further decreasing the electron density of the ring was
detrimental (13, 29%).
Further optimisation of the reaction conditions was conducted
with commercially available 8 (0.15 equiv), which improved the
yield of 2a to 64% (by 1H NMR) and 59% isolated yield, by using
palladium pivalate (10 mol%), AgTFA, and a solvent mixture of
AcOH:HFIP:H2O.[15] The use of silver salts was essential. Notably,
a similar maximum yield was achieved with acetal 12. Using these
conditions, the reaction was shown to be compatible with a range
of aryl iodides (Scheme 3).
acetal 8 or 12 (0.15 equiv)
Pd(OPiv)2 (10 mol%)
AgTFA (2 equiv)
H2N
H
H2N
Ar
ArIH
AcOH:HFIP (5:1, 0.2 M)
H2O (5 equiv), 110 °C, 18 h
(3 equiv)
1
2
acetal
2a
CO2Me 2b
8
12
acetal
8
12
59% 61%
47% 45%
32% 40%
48%
37% 46%
56%
I
I
X
H
Me
Cl
2j 56%
2k 56%
OMe 2l 47% 48%
CF3
NO2
F
2c
2d
2e
2f
I
X
Cl
X
(46% 2 mmol)
Me
F
2m 13% 26%
2n 37%
OMe 2o 38% 47%
56%
Br
I
OMe
2g
2h
2i
33% 43%
55%
I
Me
I
I
O
O
I
N
CF3
O
O
Me
2s
54%
2p
35%
47%
2q
56%
2r
57%
8:
12:
Scheme 3. Reaction scope of aryl iodides using acetals 8 and 12 as transient
directing groups.
Both directing groups 8 and 12 were investigated: acetal 12 gave
comparable and often improved yields especially for examples
when 8 was less effective. In all cases, the product amines were
isolated in analytically pure form by simple aqueous work-up,
without chromatography. Aryl iodides bearing both electron-
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10.1002/chem.201804515
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withdrawing and electron-donating functionality at the para- and
meta-positions were successful to give amines 2a-l. Halogens
were well tolerated, providing positions for further derivatisation.
Chlorophenyl derivative 2f was demonstrated on a 2 mmol scale
with 46% isolated yield, again involving only a simple work up to
provide the pure amine compound. Pleasingly, even ortho-
substituted aryl iodides (Me, F and OMe), which are often
incompatible with Pd-catalysed C–H arylation, were successful
giving 2m-o without a significant reduction in yield, particularly
using acetal 12. More complex aryl iodides were also tolerated
(2p-s), including heterocyclic derivatives.
We then investigated the amine component with
iodobenzene as the coupling partner (Scheme 4). Using
derivatives with longer alkyl substituents gave similar yields and
displayed selective arylation at the γ-CH3 position (14 and 15).
Amine 16 with a long hexyl chain gave a lower yield. Cyclohexyl
and THP containing amines were suitable substrates for the
arylation, affording 17 and 18 in good yields in this operationally
simple one-pot process. Arylation of γ-methylene positions was
not observed for any example.
products consisting of both trans- and cis-arylation as well as
further arylation on other γ-positions.
Next, structural comparisons were undertaken to indicate
the structural features of the acetal which were important in
promoting the arylation (Scheme 5). Ketal 23 did not improve the
yield above the background reaction, suggesting restricted imine
formation. Hydrocinnamaldehyde acetal 24, without the ether
oxygen, gave a lower yield than in absence of any additive,
indicating the importance of the OAr group in forming the putative
bidentate TDG. In each case, the corresponding carbonyl species
25 and 26 gave similar yields, again supporting the rapid
hydrolysis of the acetals under the reaction conditions. Catalytic
acetal 8 was shown by 1H NMR to readily hydrolyse to the
aldehyde under the reaction conditions. The use of ethers 27–29,
with similar steric and coordinating properties to acetal 8 were
unable to enhance the yield, again supporting the need for imine
formation.
additive (0.15 equiv)
Pd(OPiv)2 (10 mol%)
AgTFA (2 equiv)
H2N
H
H2N
Ph
PhI
AcOH:HFIP (5:1, 0.2 M)
H2O (5 equiv), 110 °C, 18 h
(3 equiv)
1
2a
acetal 8 or 12 (0.15 equiv)
Pd(OPiv)2 (10 mol%)
AgTFA (2 equiv)
no additive: 31%
R
R
R R
H2N
H
H2N
Ar
R
O
OMe
OMe
PhI
OMe
MeO OMe
AcOH:HFIP (5:1, 0.2 M)
H2O (5 equiv), 110 °C, 18h
R
R
R R
14-22a
O
(3 equiv)
O
Ph
OMe
Ph
8 64%
Ph
Ph
Me Ph
OMe
24 21%
R = H 27
R = Me 28
23 29%
33%
31%
H2N
Ph
H2N
Ph H2N
Ph
O
Ph
Ph
O
O
O
O
nProp
nBu
nHex
H
Ph
O
Ph
OMe
14
38%
49%
15
54%
16
19%
23%
H
Me
Ph
hydrolysis under
H2N
H2N
25 29%
26 24%
29 32%
reaction conditions
O
H2N
Ph
Scheme 5. Analysis of structural features of the optimal directing group. Yields
determined by 1H NMR using 1,3,5-trimethoxybenzene as an internal standard.
H2N
Ph
H2N
Ph
17
31%
41%
18
39%
19
20
21
30%b
33%b
33%b
(mono:di 22:8)
(mono:di 22:11)
(mono:di 19:14)
Based on these results and prior studies we propose the
reaction to be accelerated by formation of a transient imine as a
directing group. Unfortunately, attempts to isolate Pd-complexes
with the imine were unsuccessful. Therefore, we examined the
kinetics of the reaction to probe the details of the dual catalytic
cycle. To date, there are no reports of kinetic analysis on transient
C–H functionalization reactions. Blackmond pioneered reaction
progress kinetic analysis (RPKA) to make use of the kinetic
information in the full reaction profile,[16] as well as the use of
visual comparisons of concentration profiles.[17] Burés’ recent
advances have provided tools to extend the visual comparison
methods to determine reaction order for catalyst[18] and other
reaction components from reaction profiles.[19] Here, due to the
heterogeneous nature of the reactions, data was generated
through the quenching of individual reactions, monitoring
formation of arylated amine 2a.
The overall reaction profile using acetal 8 indicated that the
reaction was rapid, with maximum conversion occurring by 3 h
and little subsequent change. Unreacted t-amylamine made up
the mass-balance. Using the Burés method, the reaction was
shown to be first order in Pd, consistent with a monomeric Pd
catalyst. Surprisingly, variation in the loading of acetal 8 had little
effect: identical rates were observed at 5, 15 and 25 mol%
indicating a zero order (Figure 1).[15,20] The same rate was
NH2
NH2
acetal 8
N
[Pd]
H
Ph
PhI
arylation
conditions
OPh
22
33%
trans-product only
putative preferred
trans-intermediate
3:7
cis:trans
Scheme 4. Reaction scope of aliphatic amines. a Yields in blue refer to acetal
8, and red to acetal 12. b Using 1.5 equiv AgTFA, 3 h.
Interestingly, when using neopentylamine under our
standard conditions arylated pivaldehyde derivatives were
detected due to competing oxidation processes.[15] Therefore,
milder reaction conditions were developed for this family of
amines using a reduced reaction time and silver trifluoroacetate
loading (3 h, 1.5 equiv AgTFA) to reduce oxidation. These
afforded an improved isolated yield for arylated neopentylamine
19 (30%, combined mono and diarylation). α,β-Branched amines
were also arylated under these modified conditions to afford
products 20 and 21, both in 33% yield. When using a commercial
mixture of cis- and trans-2-methylcyclohexanamine the only
product corresponded to trans-22 (33% yield); no arylation
occurred on the cis-diastereomer indicating a high selectivity. In
comparison, under the same conditions Yu’s 2-hydroxy-
nicotinaldehyde transient directing group[11] gave a mixture of
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10.1002/chem.201804515
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observed with acetal 12, whereas the reaction was considerably
slower in the absence of the acetal (with a much lower final yield)
suggesting a different mechanism. Different excess experiments
for amine 1, PhI and AgTFA,[21] also indicated zero order in these
components. We also found identical reaction rates with different
aryl iodide species (4-iodoanisole, iodobenzene, and 4-
chloroiodobenzene).[15] The degree of stirring had little effect on
the reaction rate indicating mass transport is not rate limiting.
adjustment of the profiles, the traces did not overlay, indicating a
reduction in rate under the standard conditions at later times due
to one of these effects (Figure 2).[23] Adding the expected product
concentration from the start of the ‘same excess’ experiments
gave a profile that overlaid very well with that using the standard
conditions, showing the rate reduction was due to product
inhibition.
a)
0.1
0.08
0.06
0.04
0.02
0
starting concentrations (M)
Experiment
Standard conditions
Same Excess (1 h)
1
PhI
2a
0.183
0.110
0.110
0.548
0.475
0.475
0
0
0.12
60
0.073
Same Excess + 2a
0.1
0.08
0.06
0.04
50
25/mol%/8
15/mol%/8
0
1
2
3
4
40
t0/0h
0.16
b)
30
5/mol%/8
0.12
0.08
0.04
0
20
no/TDG
normalise for time
and expected [2a]
for comparison
0.02
0
10
0
0
1
2
t///h
3
4
0
1
2
3
4
Figure 1. Zero order rate dependence of acetal 8. Yields determined by 1H NMR
t,/,h
using 1,3,5-trimethoxybenzene as an internal standard on discrete reactions.
Figure 2. Same excess and product inhibition experiments. Showing a)
concentrations of additional product formed; and b) normalized values for direct
comparison (+1 h for and expected product concentration for same excess
experiments).[15]
To probe the C–H activation step, amine 1 was reacted with PhI
in AcOD-D4 as solvent. No D-incorporation was observed at the
benzylic position of the product, suggesting irreversible C–H
activation (Scheme 6a). Furthermore, comparison of the rate of
formation of amines 15 and D4-15 showed a faster rate for the
While product inhibition might be expected based on equilibrium
considerations, the pronounced effect suggested an additional
explanation. Therefore, we examined the interaction of the
proteo-substrate, and
a significant kinetic isotope effect
(kH/kD = 2.26, Scheme 6b). These kinetic and deuteration studies
all indicate cyclopalladation as the turnover limiting step in the
reaction.
product with palladium acetate in AcOD-D4, expecting
a
preferential complexation of the product amine with Pd over the
starting material. Mixing amine 2f with Pd(OAc)2 in a 2:1 ratio at
rt gave 3 amine species, assigned as the protonated amine, a
monoamino-Pd complex, and a palladacycle corresponding to ε-
cyclometallation (Scheme 7).[15,24] On heating at the reaction
temperature for 30 min, the aromatic signals changed to a 2H
singlet corresponding to deuteration of the ortho-positions of the
aryl group. This surprisingly facile and reversible cyclopalladation
process out-competes coordination of the substrate; deuteration
still readily occurred (40% in 30 min) in the presence of a 1:1
mixture of 1 and 2f with 10 mol% palladium. This process
represents the basis of the product inhibition in this reaction,
which is also likely to occur in related studies,[10,13] by
accumulating the Pd catalyst within these off-cycle species.
a)
8 (0.15 equiv)
Pd(OPiv)2 (10 mol%)
AgTFA (2 equiv)
H2N
H
H2N
Ph
PhI
(3 equiv)
+
+
CD3CO2D (0.2 M)
H2O (5 equiv), 110 °C
41%
H
H
1
2a
no D-incorporation
at benzylic position
b)
H2N
nBu
H
D
H2N
nBu
Ph
8 (0.15 equiv)
Pd(OPiv)2 (10 mol%)
AgTFA (2 equiv)
or
or
PhI
(3 equiv)
AcOH:HFIP (5:1, 0.2 M)
H2O (5 equiv), 110 °C
D
D
D D
H2N
nBu
H2N
nBu
Ph
kH
D
D
D D
2.26
=
kD
30/D5-30
15/D4-15
Scheme 6. Substrate deuteration and KIE.
H/D
D
Cl
Pd(OAc)2
(0.5 equiv)
H2N
110 °C
30 min
Interestingly, the addition of further acetal or Pd at later time
points in the reaction did not improve conversion,[22] posing a
question about what determined the final yield obtained. The use
of a ‘same excess’ experiment, developed by Blackmond,[16]
provided important insight. This experiment uses reduced
concentrations of the reactants to mimic starting the reaction at a
later time point (here 40% conversion; 1 h reaction time), and can
highlight catalyst deactivation or product inhibition. On time
H2N
H2N
O
Pd
work-up
AcOD
Cl
D
O
2f
D2-2f
fully deuteterated
Cl
ε-Pd-cycle
observed by 1H NMR
source of product inhibition
Scheme 7. ε-Cyclopalladation of product amine 2f.
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Based on these studies, a proposed mechanism for the dual
catalytic system is given in Scheme 8. Under the reaction
conditions, acetal 8 is hydrolysed to the corresponding aldehyde
9. The aldehyde then condenses with the free amine 1, from a
pool of the protonated amine species, to form imine I.
Complexation to the palladium catalyst with loss of a carboxylate
ligand would give a positively charged imine-Pd species II which
Conclusions
In summary, we have described the development and
mechanistic investigation of a new transient activator in palladium
catalysed C–H arylation of primary amines. The use of a bench
stable alkyl acetal acts through formation of a transient imine
directing group, with a clear influence of the (masked) aldehyde
and the aryl ether as a second coordinating group. Commercially
available (2,2-dimethoxyethoxy)benzene provides a facile and
rapid reaction of branched primary amines with a large range of
aryl iodides. Improved yields can be obtained in some cases with
(2,2-dimethoxyethoxy)-4-trifluoromethylbenzene as a modified
TDG. The C–H activation step was found to be turnover limiting,
determined by a zero-order rate dependence observed in all
reactants as well as a pronounced H/D kinetic isotope effect. The
reaction was first order in palladium catalyst. Furthermore, we
have uncovered the unexpected formation of a 7-membered
palladacycle, activating an ε-C(sp2)–H bond of the product, thus
inhibiting the reaction. We expect these insights will also feed into
future design of improved directing groups, and aid the continued
rapid progress of the field.
from
protonation
pool
Ph
OMe
OMe
Ar
H2N
H
H3O
O
O
Ph
1
8
O
9
H2N
H2O
Regeneration
of DG
H2O
Ph
2
fast
Ph
O
[Pd]
O
H
Ar
N
N
NH2R-H NH2R-Ar
H2N
AcO
V
I
O
Pd
AgI
TFA
O
Pd(O2CR)2
VI
RCO2H
AgTFA
RCO2H
Pd(OPiv)2
H2N
Ph
Pd
Ph
R
H
O
PdII
O2CR
PdIV
Ar
I
O
O
Pd(II)/Pd(IV)
redox cycle
O
O
O
VII
N
N
Experimental Section
at high [NH2R-Ar]
product inhibition
from Pd–product
complex formation
and ε-palladation
IV
II
Ph
HO2CR
PdII
turnover
limiting
O
General procedure for the Pd-catalyzed C–H arylation of
amines
N
ArI
AgTFA (132 mg, 0.60 mmol), Pd(OPiv)2 (9.3 mg, 0.03 mmol, 10
mol%), aryl iodide (3.00 equiv), H2O (27 µL, 1.50 mmol), amine
(0.30 mmol), (2,2-dimethoxyethoxy)benzene 8 (7.6 µL, 0.045
mmol), AcOH (1.25 mL) and HFIP (0.25 mL) were combined in a
microwave vial. The vial was sealed under air and the reaction
was heated at 110 °C with stirring. After 18 h, the reaction was
removed from the heat, allowed to cool to room temperature,
diluted with Et2O and filtered through a bed of Celite, eluting with
Et2O (10 mL). The product was extracted from the organic phase
into 1 M aqueous HCl solution (3 × 10 mL). The combined
aqueous extracts were basified with saturated aqueous sodium
hydroxide solution and the free amine extracted with CH2Cl2 (3 ×
15 mL). The combined organic extracts were dried (Na2SO4), and
the solvent was removed under reduced pressure to afford the
arylated product amine.
III
Scheme 8. Proposed dual catalytic cycle.
undergoes turnover-limiting cyclopalladation to afford the
cyclometalated imine intermediate III. It is likely that deprotonation
or ligand exchange occurs to form a neutral species which then
undergoes oxidative addition to PdIV intermediate IV. C–C bond
formation by reductive elimination would afford the product imine
V and regenerate the PdII catalyst. The transient directing group
is turned over by hydrolysis with water, or direct transamination,
generating the arylated product 2. The product amine inhibits the
reaction by competitive coordination to the catalyst and facile ε-
cyclometallation, removing palladium from the productive cycle.
The observed reaction profile can be rationalized by the following
assumptions. In the early stages of the reaction, when the product
concentration is low, little to no Pd-product amine complexation
occurs, and so [cat]t = [cat]0 and the increase in product
concentration is linear with zero order kinetics. However, at a
critical higher product concentration (at approx. 40% conversion),
inactive and thermodynamically favourable Pd-product
complexes are formed, removing active catalyst from the reaction
and causing a reduction in rate. Eventually, all of the catalyst is
trapped in these complexes, causing the yield to plateau. Addition
of more catalyst (10 mol%) at t = 1 h did not lead to increased
conversion; presumably also due to rapid formation of the inactive
complexes at high product concentration, or due to breakdown of
the transient aldehyde species.[15]
Acknowledgements
We gratefully acknowledge The Royal Society [University
Research Fellowship, UF140161 (to J. A. B.) and URF appointed
grant RG150444], EPSRC [CAF to J. A. B. (EP/J001538/1)], and
DTP studentship to SSJC]. We acknowledge the EPSRC UK
National Mass Spectrometry Facility at Swansea University.
Keywords: C-H Functionalization • Homogeneous catalysis •
Amines • Reaction kinetics • Palladium
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10.1002/chem.201804515
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FULL PAPER
Entry for the Table of Contents
FULL PAPER
catalytic Pd
S. St John-Campbell, A. K. Ou, and
J. A. Bull*
NH2
NH2
Ar
H
AgTFA
catalytic acetal ether
OMe
R
R
R
R
ArI
Page No. – Page No.
free 1º
amines
selective γ-C–H
functionalization
PhO
OMe
Palladium Catalyzed C(sp3)–H
Arylation of Primary Amines Using a
Catalytic Alkyl Acetal to Form a
Transient Directing Group
Single Operation Amine Arylation. The first example of an alkyl transient directing
group for palladium catalysed γ-C–H functionalisation of amines with aryl iodides is
developed. The stable acetal-ether additive is used in catalytic quantities and avoids
additional steps for directing group installation and removal. Insight into the reaction
mechanism is obtained through a combination of kinetic, deuteration and NMR
experiments.
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