Carboxylate-Assisted Oxidative Addition to Aminoalkyl PdII Complexes: C(sp3)?H Arylation of Alkylamines by Distinct PdII/PdIV Pathway

Article abstract of DOI:10.1002/anie.201902838

Reported is the discovery of an approach to functionalize secondary alkylamines using 2-halobenzoic acids as aryl-transfer reagents. These reagents promote an unusually mild carboxylate-assisted oxidative addition to alkylamine-derived palladacycles. In the presence of Ag^I salts, a decarboxylative C(sp³)?C(sp²) bond reductive elimination leads to γ-aryl secondary alkylamines and renders the carboxylate motif a traceless directing group. Stoichiometric mechanistic studies were effectively translated to a Pd-catalyzed γ-C(sp³)?H arylation process for secondary alkylamines.

Full text of DOI:10.1002/anie.201902838

A Journal of the Gesellschaft Deutscher Chemiker
Angewandte
Chemie
International Edition
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Accepted Article
Title: Carboxylate-assisted oxidative addition to aminoalkyl-Pd(II)
complexes enables catalyzed C(sp3)–H arylation of alkylamines
via distinct Pd(II)/Pd(IV) pathway
Authors: Matthew James Gaunt, William Whitehurst, John Henry
Blackwell, and Gary Hermann
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201902838
Angew. Chem. 10.1002/ange.201902838
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10.1002/anie.201902838
Angewandte Chemie International Edition
COMMUNICATION
Carboxylate-assisted oxidative addition to aminoalkyl-Pd(II)
complexes enables catalyzed C(sp3)–H arylation of alkylamines
via distinct Pd(II)/Pd(IV) pathway
William G. Whitehurst, J. Henry Blackwell, Gary N. Hermann and Matthew J. Gaunt*
Dedication ((optional))
a. Directing group-assisted strategies for C–H activation in alkylalmines
Abstract: We report the discovery of an approach to functionalize
secondary alkylamines using 2-halobenzoic acids as aryl transfer
reagents. These reagents promote an unusually mild carboxylate-
assisted oxidative addition to alkylamine-derived palladacycles. In the
presence of Ag(I) salts, a decarboxylative C(sp3)–C(sp2) bond
reductive elimination leads to γ-aryl secondary alkylamines and
N-charged–DG-neutral
N-neutral–DG-charged
N-neutral–DG-neutral
chelation, I
chelation, II
chelation, III
L
X
N
L
N
N
Pd
Pd
L
Pd
L
X
Auxiliary control:
Daugulis, Chen,
Carretero
Auxiliary control: Sanford
Transient directing group:
Yu, Ge, Young
Transient directing group:
Dong
renders the carboxylate motif
a
traceless directing group.
Stoichiometric mechanistic studies were effectively translated to a Pd-
catalyzed γ-C(sp3)–H arylation process for secondary alkylamines.
L
N
L
X
N
Pd
N
X
Pd
Pd
I
I
I
X
The transformation of unactivated C(sp3)–H bonds into C–aryl
bonds using transition metal catalysts has been the focus of
intense academic research over the past decade.[1] Within this
field, Pd-catalyzed C(sp3)–H arylation of alkylamines has
stimulated significant interest as the products of such a
transformation display structural features that are highly
represented in pharmaceutical agents.[2,3] As a general premise,
amine-directed C–H activation leads to the formation of a
palladacycle intermediate, from which arylation can be promoted
through a variety of pathways. Yu and co-workers have
established that sulfonamide and thioamide derivatives of
alkylamines undergo C–H arylation with arylboronic acids and
esters.[4] Similarly aryl iodides have been commonly employed
reagents for C(sp3)–H arylation of auxiliary-derived amine
derivatives, wherein the selective nature of the oxidative addition
to electron-rich Pd(II)-centres in the corresponding palladacycles
affords broad substrate scope and functional group
compatibility.[5] An important aspect to the reactivity of aryl iodides
is the necessary complexation of the iodide or π-system to the
metal in advance of the carbon–iodine bond cleavage.[6]
Consequently, the ligand environment in the key palladacyclic
intermediate must allow for the displacement of a neutral ligand
to promote the oxidative functionalization. In consideration of this
requirement, a number of subtly distinct strategies have been
developed for Pd-catalyzed C(sp3)–H arylation in alkylamine
derivatives and can be defined by the coordinating nature of the
directing group. Firstly, Daugulis, Chen and Carretero[5a-c] have
reported amide- and sulfonamide-linked pyridyl auxiliaries which
enable C–H activation to palladacycles comprising a bidentate
Ph
exocyclic neutral ligand (L)
exocyclic neutral ligand (L)
easily displaced, II’
oxidation requires
diaryliodonium salt, III’
easily displaced, I’
Transition states for oxidative addition of aryl iodides or iodoniums to palladacycles
charged ligand neutral ligand
b. Palladacycles of less hindered alkylamines are stable complexes – this work
aminoalkyl-palladacycles with hindered amines:
directed oxdiative addition IV’
Gaunt
H
O
R
H
N
Me
steric
destabilization
promotes
Pd
1R
X
O
stable trans
(NH)amine
configuration
R
N
O
Pd
O
N
H
R
2R
reactivity
Pr
IV
ortho-halobenzoic acid
acts as carboxylate ligand,
templating the
hypothesis
can oxidative addition to less hindered aminoalkyl-
palladacycles be facilitated by intramolecularization?
oxidative addiiton
c. Catalytic C–H arylation of less hindered amines via directed oxidative addition
R2
H
N
X
R2
H
cat. Pd(OPiv)2
4R
CO2H
3R
N
CH3
AgOAc
CHCl3, 80 ºC
–CO2
3R
R1
H
3R
R1
(NH)-alkylamine
γ-aryl-(NH)-alkylamine
Figure 1. Towards a carboxylate-assisted C–H arylation of alkylamines.
directing motif with anionic and neutral coordinating groups. The
remaining site exo to the palladacycle motif is occupied by a
neutral ligand that can be displaced by an aryl iodide, leading to
arylation (Figure 1a, I, I’). Secondly, Sanford[5g] equipped a
hindered, neutral tertiary amine derivative with an additional
anionic amide to promote the formation of a palladacycle (Figure
1a, II, II’). In a related class of C–H activation reactions, Yu, Ge
and Young[5j-m] have reported a series of transient directing
groups that lead to conceptually similar intermediates (vide supra).
In these cases, a neutral amino-derivative forms a palladacycle in
[*]
W. G. Whitehurst, J. H. Blackwell, G. N. Hermann, M. J. Gaunt
Department of Chemistry
University of Cambridge
Lensfield Road, Cambridge CB2 1EW (UK)
E-mail: mjg32@cam.ac.uk
Supporting information for this article is given via a link at the end of
the document.((Please delete this text if not appropriate))
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10.1002/anie.201902838
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COMMUNICATION
a. Pd(II)/Ag(I)-mediated C–H arylation via 7-membered palladacycle 6a
conjunction with a charged ligand, with the remaining site once
again occupied by a displaceable neutral ligand. Finally, Dong[7]
reported a variant of the transient directing group concept by
employing an imine with a tethered neutral ligand, resulting in a
palladacycle with an anionic ligand occupying the remaining site
(Figure 1a, III, III’). In this distinct scenario, the use of reactive
diaryliodonium salts is required to enable oxidation of the
palladacycle, because there is no readily displaced neutral ligand
available.[8]
Over the last five years, our laboratory has been engaged
in a research program geared towards the use of free(NH)
alkylamines in Pd(II)-catalyzed β and γ C(sp3)–H activation
reactions.[2] The success of these strategies has been dependent
on either (a) the use of hindered alkylamine substrates, which
destabilize rapidly formed bis-amine Pd(II) complexes and lead to
OPiv
Et
Pd
pyridine
Pd(OAc)2
N
N
H
CHCl3, 50 ∞C
H
O
1
2 (X-ray)
I
Me
O
I
O
OPiv
5a
H
CO2H
OPiv
O
H
O
N
N
Pd
Et
Et
Pd
(2 equiv)
N
H
N
H
H
AgOAc (1 equiv)
H
CHCl3, room temperature
–CO2
3, quantitative
6a, 75% by NMR
a
higher concentration of the mono-amine Pd(II) species
OPiv
I
empirically required for C–H activation;[9] or (b) the presence of
reagents (such as CO) that strongly impact on the mechanism of
the process.[10] While we have frequently observed stoichiometric
C–H activation with a range of alkylamines, we recognized that
the structure of a putative monocyclic aminoalkyl-palladacycle
formed in a catalytic reaction with a secondary alkylamine would
likely be reflected by a complex wherein a second molecule of
alkylamine acts as a neutral ligand alongside a charged
carboxylate ligand (Figure 1b, IV). The structural integrity of a
complex of this nature would be reinforced by the favourable
thermodynamic scenario of having opposingly dispersed
(NH)amine ligands, which replicates the profoundly stable ligand
arrangement that is observed for trans bis-amine Pd(II)
complexes.[10a,11] This effect is particularly pertinent to a potential
C–H arylation with aryl iodides, whose weak complexing ability
may not be sufficient to displace a tightly ligated-(NH)amine.
Analogous to the situation of Dong, the absence of a readily
displaced neutral ligand precludes the straightforward reaction of
the palladacycle with aryl iodides. However, strongly oxidizing
iodine(III) reagents are typically incompatible with less hindered
free(NH) alkylamines due to the presence of α-hydrogens in
Et
AcOH, rt
N
H
4a, 56%
(from 1)
AgOAc, 100 ∞C
no reaction
H
b. Structure determination of 7-membered palladacycle
F
Cl
I
O
OPiv
H
CO2H
Pd
Cl
N
N
Et
Pd
P
PAr3
H
AgOAc, CH2Cl2, rt
then NaCl
H
8 (X-ray)
7, Ar = 3,5-(CF3)2C6H3
(formed from 1, 62%)
42%
Figure 2. Stoichiometric studies from mononuclear palladacycles 3 and 7.
aminoalkyl-palladacycle 3, formed from the reaction of secondary
alkylamine 1 and Pd(OAc)2, followed by treatment of the initially
formed polynuclear species 2 with pyridine (Figure 2a). This
complex served as a characterizable model for the putative
catalytic species that would have a second molecule of the
alkylamine in place of the pyridine. Treatment of palladacycle 3
under conditions commonly used in C–H arylation reactions,
namely phenyl iodide and AgOAc (as additive) at 100 ˚C in DCE,
AcOH or as a neat reaction, gave no conversion to the
corresponding γ-aryl alkylamine 4a. As highlighted in Figure 1b, a
possible reason for the lack of reactivity of 3 is the stability
imparted by the trans orientation of nitrogen ligands on Pd(II),
meaning the iodoarene cannot displace the ligated pyridine. To
disrupt this apparently stable complex, we tested the reactivity of
an aryl iodide containing an ortho carboxylic acid, which we
reasoned would displace the acetate ligand and locate the aryl
iodide in proximity to the Pd(II) center (Figure 1b, IV’), facilitating
the oxidative addition to give the putative γ-aminoalkyl Pd(IV)
complex required for C–C bond reductive elimination. When
palladacycle 3 was treated with 2 equivalents of 2-iodobenzoic
acid 5a in the presence of one equivalent of AgOAc at room
temperature, we observed complete conversion to a 7-membered
palladacycle (6a, 75% yield by NMR).[12] Formally, the overall
transformation from 3 to 6a corresponds to a 1,2-insertion of an
aryl group into the Pd–C bond of the 5-membered palladacycle,
wherein C(sp3)–C(sp2) bond formation and an unusually facile
facilitating
decomposition
pathways.[9a,c]
Therefore,
a
conceptually distinct approach from both our previous works and
the approaches of others (vide supra) would be required to enable
free(NH) amine-directed C(sp3)–H arylation. To address the lack
of reactivity of these aminoalkyl-palladacycles towards oxidative
addition, we speculated that installing a carboxylate group at the
ortho position to the carbon–iodine bond in the aryl iodide would
displace an anionic group on the aminoalkyl-palladacycle and
promote a proximity-driven oxidative addition that could lead to
C(sp3)–H arylation (Figure 1b, IV’).
Here, we report the successful realization of these ideals,
culminating in the development of a Pd(II)-catalyzed C(sp3)–H
arylation of less hindered alkylamines. Key to the success of this
strategy is the deployment of an ortho-carboxylate-substituted
aryl halide as coupling partner, which facilitates a templated
oxidative addition to the stable aminoalkyl-palladacycle.
Furthermore, the reaction proceeds via a distinct pathway
involving a spontaneous decarboxylation and palladium migration
step, which renders the overall process traceless with respect to
the activating carboxylate motif.
At the outset of these studies, we focused on investigating
the reactivity of a representative 5-membered mononuclear γ-
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10.1002/anie.201902838
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COMMUNICATION
Figure 3. Control experiments and proposed mechanism for carboxylate-assisted C–H arylation.
decarboxylation event have taken place. Palladacycle 6a was
isolable and could be characterized by 1H and 13C NMR
spectroscopy; although 6a was not a crystalline compound, the
structure of a related phosphine-ligated 7-membered palladacycle
8 could be confirmed through X-ray diffraction of a single crystal
(Figure 2b). Consequently, treatment of palladacycle 6a with
AcOH gave γ-aryl alkylamine 4a (56% yield from 1), completing
the overall C–H arylation process.
reductive elimination from a putative Pd(IV) species would initially
install an aryl-2-carboxylic acid group at the γ position, giving an
amino acid intermediate that may then undergo a known Pd(II)-
or Ag(I)-mediated decarboxylation process to form the γ-arylated
amine.[17] To test this hypothesis, amino acid 9 was synthesized
and subjected to stoichiometric quantities of Pd(OAc)2 and
AgOAc (Figure 3b). Although minimal conversion occurred at
room temperature, stirring the reaction at 80 oC led to the
formation of a new palladacyclic species (10) resulting from a
methylene C–H activation. Crucially, given that the product of
decarboxylation (4a) was not observed, the hypothesis invoking
amino acid 9 as an intermediate was not supported. Rather, it
became apparent that decarboxylation must occur prior to C–C
bond reductive elimination and therefore from a high valent Pd(IV)
species, which could explain the facile nature of this process
compared to reported decarboxylation procedures that typically
Intrigued by the formation of the 7-memebred palladacycle,
we conducted a series of control experiments to shed light on the
mechanistic steps underpinning the decarboxylative arylation
process. Firstly, subjecting 3 to 2-bromobenzoic acid instead of 2-
iodobenzoic acid simply resulted in a ligand exchange of acetate
for 2-bromobenzoate at room temperature, with the 5-membered
(NH)amine palladacycle remaining intact.[13] Stirring the reaction
o
at 80 C restored reactivity analogous to that of the aryl iodide,
o
which is consistent with a Pd(II)–Pd(IV) mechanism based on the
diminished reactivity of the aryl bromide relative to the iodide.[14]
Secondly, using 5-methyl-2-iodobenzoic acid 5b as coupling
partner, the arylated product was formed as a single regioisomer
(4b) in which the newly formed C–C bond is derived from the C–I
bond in the reagent (Figure 3a). The exclusive regioselectivity
observed cannot be accounted for by a mechanism invoking
aryne intermediates, as this would generate regioisomeric
product mixtures.[15] Further evidence opposing aryne formation
was provided by trapping experiments employing arynophile
additives in the stoichiometric arylation procedure, which did not
lead to the formation of cycloaddition by-products.[16] Thirdly, we
investigated the point at which decarboxylation occurs along the
reaction pathway. Intuitively, one might assume that C–C bond
require high temperatures (>100 C).[17] Lastly, replacing AgOAc
with NaOAc led to a significant change in the distribution of
products (Figure 3c); C–O coupled products 11 (43%) and 12
(10%) as well as elimination product 13 (10%) were obtained.
According to literature precedence, C–O reductive elimination is
expected to proceed via external attack of an O-centred
nucleophile at the Pd(IV)-bound carbon (int-I),[18] thus accounting
for the presence of the ortho-iodide moiety in major product 11.
Notably, arylated product 4a was not observed in the reaction with
NaOAc, and therefore in the current system Ag(I) was found to be
an essential additive for C–C bond reductive elimination.
Based on these preliminary mechanistic studies, we
propose a pathway that first involves carboxylate-directed
oxidative addition (via int-II) to form the bis-palladacyclic γ-
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10.1002/anie.201902838
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COMMUNICATION
Table 1. Scope of the Pd-catalyzed C(sp3)–H arylation of alkylamines.[a]
O
Br
R2
R2
H
N
H
N
Pd(OPiv)2 (10 mol%)
4R
4R
HO
CH3
AgOAc (2 equiv)
CHCl3, 80 ºC, 20 h
3R
R1
3R
R1
(NH)-alkylamine
(2 equiv)
γ-aryl-(NH)-alkylamine
aryl scope
amine scope
OPiv
Et
OPiv
Et
O
O
Me
Me
F
F
4a, R = H, 70%
4b, R = Me, 66%
4c, R = F, 54%
4d, R = OMe, 54%
4e, R = CF3, 39%
Br
N
H
N
5
H
HO2C
1
R
R
14a, 65%
Me
14b, 62%
14c, 37%
14d, 72%
R
R
F
O
4
Br
OPiv
Et
Me
Me
O
TsN
Me
Me
Br
O
HO2C
1
Me
F
N
H
HO2C
1
6
14g, 74%
14h, 56%
14i, 40%
14j, 43%
14e, 72%
14f, 77%
4fa, R = Me, 63%
4g, R = F, 56%
4h, R = Cl, 61%
4i, R = Br, 49%[b]
Me
4fb, 60%
OPiv
H
R
O
OPiv
Et
Et
OBz
OMe
N
N
H
N
O
R
3
H
N
H
4j, R = F, 46%
4k, R = OMe, 51%
(R = Me, 0%)
Br
14k
57%
14l
58%
14m, 53%[c]
14n, 0%
HO2C
1
R
OPiv
OPiv
OtBu
OPiv
Et
OPiv
Et
60%[d]
2:1 mono:di
(mono d.r. 1:1)
4
5
Br
OMe
OMe
N
H/Ph
N
H
N
H
4l, 61%
N
H
H
HO2C
1
OMe
OMe
14o, 45%
14p
14q, 65%
[a] Reactions carried out on 0.1 mmol scale. [b] 2.5 equiv Ar–Br and 2.5 equiv AgOAc were used. [c] Reaction temperature was 70 ˚C. [d] Yield and d.r. determined
by 1H NMR analysis of the crude reaction mixture.
aminoalkyl-Pd(IV) species int-III (Figure 3d). Presumably, Ag(I)-
mediated iodide-to-carboxylate ligand exchange generates the
corresponding Pd(IV)-carboxylate complex, which through
pyridine-displacing κ2-carboxylate binding, can trigger a series of
geometric isomerizations to form hydrogen bond-stabilized Pd(IV)
intermediate int-IV. C(sp3)–C(sp2) bond reductive elimination
from int-IV does not occur, most likely due to the geometric
constraints of the bis-palladacycle. However, based on the
observed regioselectivity and the absence of aryne intermediates,
zero product formation.[21] Optimal conditions required the
treatment of amine 1 with 10 mol% Pd(OPiv)2, 2 equivalents of 2-
bromobenzoic acid and 2 equivalents of AgOAc in CHCl3 at 80 ˚C
for 20 h, affording 4a in 74% yield by NMR (70% isolated yield,
Table 1).
With the optimal conditions for C–H arylation identified, the
scope of aryl reagents was investigated (Table 1). Electron-
donating and -withdrawing substituents at the 4- and 5-positions
of the 2-bromobenzoic acid were well tolerated, affording meta-
and para-substituted arylated products in moderate to good yields
(4b–i). Interestingly, 2-bromo-6-methylbenzoic acid was an
effective reagent, demonstrating that increased steric bulk ortho
to the carboxylic acid is tolerated. The meta-methyl product was
formed in similar yield (60%, 4fb) to the reaction using 2-bromo-
4-methylbenzoic acid (63%, 4fa), which gives the same product
after decarboxylation. Conversely, the reaction was sensitive to
steric effects at the position ortho to the C–Br bond. While ortho-
fluoride and -methoxy derivatives could be obtained in moderate
yields (4j, 4k), 2-bromo-3-methylbenzoic acid gave no reactivity.
Finally, 2-bromo-4,5-dimethoxybenzoic acid gave access to more
highly substituted derivative 4l.
we believe
a decarboxylation triggers a concerted 1,2-
arylpalladium migration and reductive elimination, forging (i) the
C(sp3)–C(sp2) bond between the alkylamine and aryl group and
(ii) the ortho C(sp2)–Pd bond, giving the 7-memebered
palladacycle (6b). To the best of our knowledge, 1,2-
arylpalladium migrations have been rarely observed outside the
context of norbornene-assisted Catellani processes,[19] despite
the analogy with commonly encountered 1,2-palladium migrations
on indole or of alkenyl-Pd(II) species.[20]
Next, we tested the decarboxylative C–H arylation under
catalytic conditions. Gratifyingly, using 10 mol% Pd(OAc)2 in the
presence of amine 1, 2-iodobenzoic acid 5a and AgOAc in CHCl3
o
at 80 C gave arylated product 4a in 51% yield by NMR. C–O
The scope of amine substrates was also investigated (Table
1). A range of functional groups was tolerated in the non-
activating substituent of the substrates (14a–j), including alkyl,
fluoroalkyl, ketal, ether and sulfonamide groups. Cyclic as well as
coupling was observed as a minor side reaction (11, 8%).
Significantly, the use of 2-bromobenzoic acid gave an increased
yield of 4a, whereas 2-chloro- and 2-(OTf)benzoic acid resulted in
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10.1002/anie.201902838
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COMMUNICATION
[4]
[5]
a) M. Wasa, K. M. Engle, J.-Q. Yu, Isr. J. Chem. 2010, 50, 605-616; b)
K. S. L. Chan, M. Wasa, L. Chu, B. N. Laforteza, M. Miura, J.-Q. Yu, Nat.
Chem. 2014, 6, 146-150; c) J. E. Spangler, Y. Kobayashi, P. Verma, D.-
H. Wang, J.-Q. Yu, J. Am. Chem. Soc. 2015, 137, 11876-11879; d) Q.
Shao, J. He, Q.-F. Wu, J.-Q. Yu, ACS Catal. 2017, 7, 7777-7782; e) Q.
Shao, Q.-F. Wu, J. He, J.-Q. Yu, J. Am. Chem. Soc. 2018, 140, 5322-
5325.
acyclic sidechains could be incorporated. Generally, n-alkyl
substituents were not tolerated, though an N-benzyl derivative
gave a moderate yield of the arylated product (14j, 43%). Various
substituents could be tolerated along the activating chain,
including benzoate, methyl ether and phthalimide groups (14k–
m). A substrate without β-branching gave no conversion to the
corresponding arylated product (14n), whereas a substrate
derived from the non-natural diastereomer of isoleucine gave an
average yield in the reaction (14o, 45%). A valinol derivative was
also suitable and gave 14p as a mixture of diastereomers and
mono-/di-arylated products (60% by NMR, 2:1 mono:di, mono d.r.
= 1:1). Finally, we were pleased to find that a derivative of
threoninol gave the γ-aryl amino alcohol product in good yield
(14q, 65%).
a) V. G. Zaitsev, D. Shabashov, O. Daugulis, J. Am. Chem. Soc. 2005,
127, 13154-13155; b) G. He, G. Chen, Angew. Chem. Int. Ed. 2011, 50,
5192-5196; c) N. Rodríguez, J. A. Romero-Revilla, M. A. Fernández-
Ibáñez, J. C. Carretero, Chem. Sci. 2013, 4, 175-179; d) M. Fan, D. Ma,
Angew. Chem. Int. Ed. 2013, 52, 12152-12155; e) P.-X. Ling, S.-L. Fang,
X.-S. Yin, K. Chen, B.-Z. Sun, B.-F. Shi, Chem. Eur. J. 2015, 21, 17503-
17507; f) J. Han, Y. Zheng, C. Wang, Y. Zhu, D.-Q. Shi, R. Zeng, Z.-B.
Huang, Y. Zhao, J. Org. Chem. 2015, 80, 9297-9306; g) J. J. Topczewski,
P. J. Cabrera, N. I. Saper, M. S. Sanford, Nature 2016, 531, 220-224; h)
N. Gulia, O. Daugulis, Angew. Chem. Int. Ed. 2017, 56, 3630-3634; i) A.
Yada, W. Liao, Y. Sato, M. Murakami, Angew. Chem. Int. Ed. 2017, 56,
1073-1076; j) Y. Wu, Y.-Q. Chen, T. Liu, M. D. Eastgate, J.-Q. Yu, J. Am.
Chem. Soc. 2016, 138, 14554-14557; k) Y. Liu, H. Ge, Nat. Chem. 2017,
9, 26-32; l) M. Kapoor, D. Liu, M. C. Young, J. Am. Chem. Soc. 2018,
140, 6818-6822; m) Y.-Q. Chen, Z. Wang, Y. Wu, S. R. Wisniewski, J. X.
Qiao, W. R. Ewing, M. D. Eastgate, J.-Q. Yu, J. Am. Chem. Soc. 2018,
140, 17884-17894.
In summary, we have described a new method for C(sp3)–
H
arylation of free(NH) secondary amines mediated by
Pd(II)/Ag(I) using 2-halobenzoic acid reagents. Stoichiometric
studies from the Pd(II) metallacycle demonstrated a remarkably
mild, room temperature decarboxylative arylation is possible
when using 2-iodobenzoic acid in the presence of AgOAc.
Mechanistic studies suggest that the decarboxylation occurs from
a high valent Pd(IV) centre and that a 1,2-arylpalladium migration
ultimately leads to the required reductive elimination event. The
conditions were found to effectively translate to a catalytic system,
providing access to a variety of γ-arylated amine derivatives.
[6]
a) F. Barrios-Landeros, J. F. Hartwig, J. Am. Chem. Soc. 2005, 127,
6944-6945; b) H. M. Senn, T. Ziegler, Organometallics 2004, 23, 2980-
2988; c) P. Sehnal, R. J. K. Taylor, I. J. S. Fairlamb, Chem. Rev. 2010,
110, 824-889.
[7]
[8]
[9]
Y. Xu, M. C. Young, C. Wang, D. M. Magness, G. Dong, Angew. Chem.
Int. Ed. 2016, 55, 9084-9087.
a) K. J. Szabó, J. Mol.Catal. A: Chem. 2010, 324, 56-63; b) N. R. Deprez,
M. S. Sanford, Inorg. Chem. 2007, 46, 1924-1935.
Acknowledgements
a) A. McNally, B. Haffemayer, B. S. L. Collins, M. J. Gaunt, Nature 2014,
510, 129-133; b) A. P. Smalley, M. J. Gaunt, J. Am. Chem. Soc. 2015,
137, 10632-10641; c) J. Calleja, D. Pla, T. W. Gorman, V. Domingo, B.
Haffemayer, M. J. Gaunt, Nat. Chem. 2015, 7, 1009-1016.
We are grateful to EPSRC (EP/N031792/1) and for a studentship
(W.G.W.), AstraZeneca for a studentship (J.H.B.), the German
Academic Exchange Service (DAAD) for a scholarship (G.N.H.),
and the Royal Society for a Wolfson Merit Award (M.J.G.) for
funding. We are grateful to the mass spectrometry service at the
University of Swansea and to Dr Andrew D. Bond for X-ray
crystallographic analysis. We are grateful for useful discussion
with Dr Charlene Fallan and Dr Thomas Hunt (AstraZeneca).
[10] a) D. Willcox, B. G. N. Chappell, K. F. Hogg, J. Calleja, A. P. Smalley, M.
J. Gaunt, Science 2016, 354, 851-856; b) J. R. Cabrera-Pardo, A.
Trowbridge, M. Nappi, K. Ozaki, M. J. Gaunt, Angew. Chem. Int. Ed.
2017, 56, 11958-11962.
[11] a) A. D. Ryabov, Chem. Rev. 1990, 90, 403-424; b) R. A. Widenhoefer,
S. L. Buchwald, Organometallics 1996, 15, 3534-3542; c) J. Dupont, C.
S. Consorti, J. Spencer, Chem. Rev. 2005, 105, 2527-2571.
[12] Under otherwise identical conditions, reaction of 3 with diphenyliodonium
triflate gave no conversion to 4a. Heating to 80 oC for 16 h resulted in full
consumption of 3 and 24% yield of 4a by NMR.
Keywords: C–H activation • palladium • palladacycle •
alkylamine • decarboxylation
[13] See the Supplementary Information for details of the control experiment
of 3 with 2-bromobenzoic acid.
[1]
a) O. Daugulis, H.-Q. Do, D. Shabashov, Acc. Chem. Res. 2009, 42,
1074-1086; b) X. Chen, K. M. Engle, D.-H. Wang, J.-Q. Yu, Angew.
Chem. Int. Ed. 2009, 48, 5094-5115; c) T. W. Lyons, M. S. Sanford,
Chem. Rev. 2010, 110, 1147-1169; d) O. Baudoin, Chem. Soc. Rev.
2011, 40, 4902-4911; e) K. M. Engle, T.-S. Mei, M. Wasa, J.-Q. Yu, Acc.
Chem. Res. 2012, 45, 788-802; f) O. Daugulis, J. Roane, L. D. Tran, Acc.
Chem. Res. 2015, 48, 1053-1064; g) G. Qiu, J. Wu, Org. Chem. Front.
2015, 2, 169-178; h) G. He, B. Wang, W. A. Nack, G. Chen, Acc. Chem.
Res. 2016, 49, 635-645; i) J. He, M. Wasa, K. S. L. Chan, Q. Shao, J.-Q.
Yu, Chem. Rev. 2017, 117, 8754-8786; j) Y. Xu, G. Dong, Chem. Sci.
2018, 9, 1424-1432; k) J. C. K. Chu, T. Rovis, Angew. Chem. Int. Ed.
2018, 57, 62-101; l) T. G. Saint-Denis, R.-Y. Zhu, G. Chen, Q.-F. Wu, J.-
Q. Yu, Science 2018, 359, eaao4798.
[14] J. Vincente, A. Arcas, F. Juliá-Hernández, D. Bautista, Angew. Chem. Int.
Ed. 2011, 50, 6896-6899.
[15] a) R. Huisgen, J. Sauer, Angew. Chem. 1960, 72, 91-108; b) E. R. Biehl,
E. Nieh, K. C. Hsu, J. Org. Chem. 1969, 34, 3595-3599; c) J. L.
Henderson, A. S. Edwards, M. F. Greaney, J. Am. Chem. Soc. 2006, 128,
7426-7427; d) J. L. Henderson, A. S. Edwards, M. F. Greaney, Org. Lett.
2007, 9, 5589-5592; e) J.-A. García-López, M. F. Greaney, Chem. Soc.
Rev. 2016, 45, 6766-6798.
[16] See the Supplementary Information for aryne trapping experiments.
[17] a) N. Rodríguez, L. K. Goossen, Chem. Soc. Rev. 2011, 40, 5030-5048;
b) J. Cornella, I. Larrosa, Synthesis 2012, 44, 653-676; c) G. J. P. Perry,
I. Larrosa, Eur. J. Org. Chem. 2017, 3517-3527; d) M. Font, J. M. Quibell,
G. J. P. Perry, I. Larrosa, Chem. Commun. 2017, 53, 5584-5597.
[18] a) N. M. Camasso, M. H. Pérez-Temprano, M. S. Sanford, J. Am. Chem.
Soc. 2014, 136, 12771-12775; b) M. Nappi, C. He, W. G. Whitehurst, B.
G. N. Chappell, M. J. Gaunt, Angew. Chem. Int. Ed. 2018, 57, 3178-3182.
[2]
[3]
C. He, W. G. Whitehurst, M. J. Gaunt, Chem 2019, DOI:
10.1016/j.chempr.2018.12.017.
a) S. D. Roughley, A. M. Jordan, J. Med. Chem. 2011, 54, 3451-3479; b)
E. Vitaku, D. T. Smith, J. T. Njardarson, J. Med. Chem. 2014, 57, 10257-
10274; c) D. C. Blakemore, L. Castro, I. Churcher, D. C. Rees, A. W.
Thomas, D. M. Wilson, A. Wood, Nat. Chem. 2018, 10, 383-394.
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[19] a) E. A. Filatova, A. V. Gulevskaya, A. F. Pozharskii, V. A. Ozeryanskii,
Tetrahedron 2016, 72, 1547-1557; b) M. Catellani, E. Motti, N. Della Ca’,
Acc. Chem. Res. 2008, 41, 1512-1522.
Am. Chem. Soc. 2007, 129, 6931-6942; c) A. T. Lindhardt, T. M. Gøgsig,
T. Skrydstrup, J. Org. Chem. 2009, 74, 135-143.
[21] See the Supplementary Information for full details of the optimization of
the Pd-catalyzed C(sp3)–H arylation reaction.
[20] a) B. S. Lane, M. A. Brown, D. Sames, J. Am. Chem. Soc. 2005, 127,
8050-8057; b) J.-P. Ebran, A. L. Hansen, T. M. Gøgsig, T. Skrydstrup, J.
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Title
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H
O
cat. Pd(OPiv)2, AgOAc
CHCl3, 80 ºC
R
R2
H
N
R2
N
H
N
Pd
X
4R
4R
CH3
O
X
Page No. – Page No.
3R
R1
H
3R
R1
CO2H
traceless
carboxylate-assisted
oxidative addition
Title
amine
γ-arylated amine
30 examples
ortho-halobenzoic acid
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