Carbon Dioxide-Mediated C(sp2)-H Arylation of Primary and Secondary Benzylamines

Article abstract of DOI:10.1021/jacs.9b03375

C-C bond formation by transition metal-catalyzed C-H activation has become an important strategy to fabricate new bonds in a rapid fashion. Despite the pharmacological importance of ortho-arylbenzylamines, however, effective ortho-C-C bond formation of free primary and secondary benzylamines using Pd^II remains an outstanding challenge. Presented herein is a new strategy for constructing ortho-arylated primary and secondary benzylamines mediated by carbon dioxide (CO₂). The use of CO₂ with Pd is critical to allowing this transformation to proceed under relatively mild conditions, and mechanistic studies indicate that it (CO₂) is directly involved in the rate-determining step. Furthermore, the milder temperatures furnish free amine products that can be directly used or elaborated without the need for deprotection. In cases where diarylation is possible, an interesting chelate effect is shown to facilitate selective monoarylation.

Full text of DOI:10.1021/jacs.9b03375

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Article
Carbon Dioxide-Mediated C(sp2)–H Arylation
of Primary and Secondary Benzylamines
Mohit Kapoor, Pratibha Chand-Thakuri, and Michael C. Young
J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 29 Apr 2019
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Journal of the American Chemical Society
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Carbon Dioxide-Mediated C(sp2)–H Arylation of Primary and
Secondary Benzylamines
Mohit Kapoor,‡ Pratibha Chand-Thakuri,‡ and Michael C. Young*
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Department of Chemistry and Biochemistry, School of Green Chemistry and Engineering, University of Toledo, Toledo,
OH, 43606.
ABSTRACT: C–C bond formation by transition metal-catalyzed C–H activation has become an important strategy to fabricate new
bonds in a rapid fashion. Despite the pharmacological importance of ortho-arylbenzylamines, however, effective ortho-C–C bond
formation of free primary and secondary benzylamines using PdII remains an outstanding challenge. Presented herein is a new strategy
for constructing ortho-arylated primary and secondary benzylamines mediated by carbon dioxide (CO2). The use of CO2 with Pd is
critical to allowing this transformation to proceed under relatively mild conditions, and mechanistic studies indicate that it (CO2) is
directly involved in the rate determining step. Furthermore, the milder temperatures furnish free amine products that can be directly
used or elaborated without the need for deprotection. In cases where diarylation is possible, an interesting chelate effect is shown to
facilitate selective monoarylation.
■ INTRODUCTION
Amines are a ubiquitous functional group, being
ortho-arylation utilizing free primary and secondary
benzylamines as substrates.42 Though the arylation strategy was
successful, the harsh conditions led to partial protection of the
substrate and product as acetamides, which led to the need to
fully protect the amines for isolation. Furthermore, the substrate
scope of secondary amines was only demonstrated for N-
methylbenzylamines. Subsequent strategies have emerged for
C–H arylation,43, 44 carbonylation,45 olefination,46 and even a
Catellani-type reaction47 of tertiary benzylamines using Pd as a
5
especially important in polymers1-3 and pharmaceuticals.4,
Despite many classical6-8 and modern9-12 approaches to their
synthesis, however, new methods are still in demand to access
new chemical space surrounding these functional groups.13 One
strategy for preparing amines that has recently been gaining
traction has been to functionalize C–H bonds through C–H
activation14-17 and C–H functionalization18-20 methods. These
approaches can allow rapid access to compounds that were
either inaccessible with conventional synthetic methods, or
required more lengthy synthetic routes, thereby expediting and
improving drug library synthesis.21 Although primary and
secondary aliphatic amines often require pre-functionalization
with static directing groups to facilitate C–H bond activation
and prevent undesirable substrate oxidation under palladium-
catalyzed protocols,22-29 aromatic C–H bonds have generally
been more easily targeted. For this reason free
homobenzylamines30, 31 have been widely used as substrates for
a variety of palladium-catalyzed C–H activation reactions
without the need to pre-functionalize the amine. It is therefore
interesting to note that there was until recently no example in
the literature whereby free primary ortho-aryl benzylamines
could be directly accessed via C–H arylation,32 and there is still
no method for the same transformation on free secondary
benzylamine substrates. Because of the importance of the biaryl
moiety in a number of biologically-active molecules (Figure
1),33-35 we considered that the ability to directly access free
primary and secondary ortho-aryl benzylamines directly under
milder conditions would have utility to the synthetic
community.
catalyst,
as
well
as
one
example
of
the
carbonylation/lactamization of free primary benzylamines,48
yet no improvements have been made on C–H arylation of
secondary benzylamines, and only one report has improved on
the arylation of primary benzylamines.32 Notably, while this
manuscript was under review, two reports were published
demonstrating minimal examples of ortho-C(sp2)–H arylation
of benzylamines, albeit at higher temperatures49 or requiring a
more exotic Ar+ reagent.50
Figure 1. Examples of Biologically Active ortho-Aryl
Benzylamines.
MeO
HOOC
HO
O
O
H
O
MeO
MeO
N
O
N
O MeO
N
F3C
O
O
O
CF3
O
OH
HO
(-)-Steganacin
aza-analogue
Ortho-aryl benzylamines are generally prepared directly
Dalomycin T
-Secretase Modulators
from biaryl nitriles via reduction36, 37 or an azidation/reduction

sequence, also from
a
pre-formed biaryl species.38
Present efforts in the field of C–H activation field have
moved towards use of transient directing groups that can be
formed in situ.51 Though more frequently applied to aldehyde52-
54 and ketone55-57-based substrates, this has also been achieved
more recently using amine substrates combined with aldehyde-
Alternatively, they can be prepared from protected
40
benzylamines via Suzuki-Miyaura cross-coupling39,
or
directed C–H arylation.41 However, it was not until 2006 that
Daugulis was able to show the first example of Pd-catalyzed
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Page 2 of 11
based directing groups.32, 58-63 Inspired by this and the use of
CO2 as a traceless directing group for C–H activation of
phenols,64, 65 we recently developed a different approach, and
showed that γ-arylation of aliphatic amines could be achieved
in the presence of carbon dioxide.66 Mechanistic experiments
surrounding that work supported the idea of a transient
carbamate serving as a directing as well as protecting group,
thereby facilitating the desired C–H activation step. We
therefore considered that carbon dioxide might facilitate the
realization of a milder C–H activation strategy towards free
primary and secondary ortho-arylbenzylamines.
Reactions set-up using amine (0.15 mmol), halide (0.45 mmol), Pd
1
2
3
4
5
6
7
8
precatalyst (0.015 mmol), CO2 (~0.75 mmol), H2O (0.60 mmol), 1
mL of solvent, followed by running at 100 ºC for 12h. a NMR yields
determined using 1,1,2,2-tetrachloroethane as an internal standard.
b 24 h reaction time. c 110 ºC reaction temperature. d 90 ºC reaction
temperature. e 1.5 equiv. of Ag additive used. f No dry ice added.
We next explored whether the relative acidity of the
solution was important, and began testing different mixtures of
AcOH and HFIP (Entries 9 – 13). Although higher amounts of
AcOH seemed detrimental to the reaction, a mixture of HFIP
and AcOH was found to improve the overall yield, with the best
coming from a mixture of 7:3 HFIP/AcOH (Entry 11). Despite
the potential for ion exchange, the palladium precursor is
important to the reaction, with the dichloride or
bis(trifluoroacetate) salts performing poorly (Entries 14 and
15). Although Ag salts are sometimes used simply as halide
scavengers,69 the yield was decreased when only 1.5 equivalents
of silver trifluoroacetate was added (Entry 16), and less than
one turnover was achieved when silver trifluoroacetate was
omitted (Entry 17), suggesting more than one role in this
transformation. Consistent with our hypothesis, the reaction is
greatly enhanced by CO2, and only 9% yield was obtained in
the absence of additional CO2 (Entry 18), while omission of
palladium completely shut down the reaction (Entry 19).
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■ RESULTS AND DISCUSSION
To investigate the feasibility of utilizing carbon dioxide to
facilitate the γ-C(sp2)–H arylation of benzylamines, we focused
on the substrate 2-(2-fluorophenyl)butan-2-amine. We were
delighted to find that our previously reported conditions for
aliphatic amines, using Pd(OAc)2 as pre-catalyst, AgTFA as an
additive, and acetic acid as solvent, gave product albeit in only
modest yield (Table 1, Entry 1). The reaction was performed
in a 2 dram reaction vial by combination of the reagents and
solvent, followed by addition of carbon dioxide in the form of
dry ice.67 Despite numerous examples in our previous report
where C(sp3)‒H arylation was exclusively observed for
secondary benzylamines (presumably due to possessing a more
favorable conformation),68 only C(sp2)‒H arylation was
observed in the current examples. We examined other less
Lewis acidic Ag salts (Entries 2 and 3), but found them to give
poorer results. Increasing the halide loading to 3 equivalents
gave improved yield, with only marginal improvement when
the reaction time was extended to 24 h (Entries 4 and 5).
Table 2. Aryl Iodide Scope of the γ-C(sp2)‒H Arylation of 2-
(2-Fluorophenyl)butan-2-amine.
F
NH2
I
Pd(OAc)2 (10 mol%)
AgTFA (2.0 equiv.)
F
NH2
+
R
CO2, H2O
HFIP/AcOH
Changing
the
solvent
to
HFIP
(1,1,1,3,3,3-
R
1a-z
hexafluoroisopropanol) gave a dramatic increase in yield, with
the optimal temperature to perform the reaction being 100 ºC
(Entries 6 – 8).
CF3
F
F
Table 1. Optimization of the C–H Arylation of 2-(2-
Fluorophenyl)butan-2-amine with Ethyl 4-Iodobenzoate.
1c, 63%
1d, 69%
1a, 71%
1e, 61%
1b, 64%
CO2Et
F
F
NH2
I
F
NH2
Pd-catalyst (10 mol%)
Ag-salt (2.0 equiv.)
CO2Et
CF3
+
F
CO2, H2O
Solvent
1g, 73%
1h, 77%
1f, 55%
CO2Et
CO2Et
CO2Me
NO2
Pd-catalyst
Ag-salt Yield (%)a
Halide (equiv.)
Solvent
Entry
1
Me
2.0
1.5
1.5
3.0
Pd(OAc)2
Pd(OAc)2
27
AcOH
AcOH
AcOH
AcOH
AcOH
HFIP
AgTFA
NO2
5
2
Ag2CO3
O
CO2Me
1l, 64%
17
3
Pd(OAc)2
Pd(OAc)2
AgOAc
1k, 64%
1i, 57%
1j, 51%
34
38
71
66
4
5b
AgTFA
AgTFA
AgTFA
AgTFA
Me
3.0
3.0
3.0
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
6
7c
N
Br
1m, 72%
I
Ts
HFIP
8d
9
AgTFA
AgTFA
1o, 49%
1p, 75%
OCHF2
1n, 70%
OMe
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
3.0
3.0
59
52
HFIP
HFIP/AcOH(1:1)
3.0
3.0
3.0
3.0
3.0
3.0
63
78
77
10
11
12
HFIP/AcOH(6:4)
HFIP/AcOH(7:3)
HFIP/AcOH (8:2)
AgTFA
AgTFA
AgTFA
AgTFA
OMe
Me
1s, 59%
1t, 57%
1q, 81%
1u, 57%
1r, 61%
75
22
29
57
13
14
15
HFIP/AcOH (9:1)
HFIP/AcOH (7:3)
HFIP/AcOH (7:3)
Pd(OAc)2
PdCl2
Pd(TFA)2
N
AgTFA
AgTFA
AgTFA
--
H
H
16e HFIP/AcOH (7:3)
17
HFIP/AcOH (7:3)
18f HFIP/AcOH (7:3)
19
HFIP/AcOH (7:3)
3.0
3.0
3.0
3.0
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
--
N
H
5
AgTFA
Ph
1w, 66%
9
0
OCHF2
OCF3
O
O
AgTFA
1v, 59%
1x, 34%
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Reactions set-up using amine (0.15 mmol), halide (0.45 mmol),
Reactions set-up using amine (0.15 mmol), halide (0.45 mmol),
1
2
3
4
Pd(OAc)2 (0.015 mmol), AgTFA (0.30 mmol), CO2 (~0.75 mmol),
H2O (0.60 mmol), 1 mL of HFIP/AcOH (7:3), followed by running
at 100 ºC for 12-15h. Reactions were run in duplicate and the
average yield reported.
Pd(OAc)2 (0.015 mmol), AgTFA (0.30 mmol), CO2 (~0.75 mmol),
H2O (0.60 mmol), 1 mL of HFIP/AcOH (7:3), followed by running
at 100 ºC for 12-15h. Reactions were run in duplicate and the
average yield reported.
5
6
7
8
With the optimized conditions in hand, we next set-out to
explore the substrate scope of the transformation with regard to
aryl halides (Table 2). Using the optimized conditions, phenyl
iodide could be coupled with 2-(2-fluorophenyl)butan-2-amine
in 71% isolated yield (1a). The reaction could be performed on
a number of fluorinated aryl iodides (1b – 1f), as well as those
with more electron deficient groups such as esters (1g and 1h),
nitro groups (1i and 1j), ketones (1k), and even multiple
electron deficient groups (1l). It is noteworthy that neither the
ketone nor the isophthalate groups show signs of condensation
or substitution with the amine under the reaction conditions.
Reactions with either bromoiodobenzene (1m) or
diiodobenzene (1n) could be performed without reactivity at the
second halogen. Electron rich aryl iodides bearing indole rings
(1o), methyl groups (1p and 1q), methoxy groups (1r and 1s),
both difluoro and trifluoromethoxy groups (1t – 1v), and even
an arene with extended conjugation (1w) were also tolerated
during the reaction. Surprisingly, 2-iodostrychnine70 can be
used in the reaction (1x) despite the presence of a tertiary amine
that can also react with CO2. Furthermore, the conditions are
mild enough to preserve both the amide and allylic ether groups.
Although the alkene is preserved in the case of 1x, many other
alkene-containing substrates were unsuitable for the reaction.71
It is worth noting that N-heterocyclic substrates, including 3-
iodopyridine and 2-iodoquinoline, did not give any identifiable
product under these reaction conditions, most likely due to
competitive binding or poisoning of the palladium catalyst.72
We next focused on the scope of the reaction with respect
to the amine substrates. A common issue in the intermolecular
o-C(sp2)‒H activation literature is the challenge of achieving
selective monofunctionalization, and so we initially focused on
examples that would be unlikely to undergo diarylation by
positioning a group at either the 2 or 3 position of the
benzylamine.73 Short to medium length aliphatic chains could
be tolerated, all with excellent selectivity for C(sp2)‒H arylation
(Table 3, 2a – 2d). Moving the position of the fluoro substituent
on the benzylamine (2e) as well as using substrates bearing
either an o- or m-chloro group (2f and 2g) all gave good yields.
More electron rich benzylamines with methyl (2h) and methoxy
(2i) substituents were also tolerated in the reaction. Amines
with both benzylic and homobenzylic sites showed complete
selectivity for γ-arylation on the benzyl rather than δ-arylation
on the homobenzylic chain (2j and 2k), presumably due to a
faster rate of C‒H activation.
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Gratifyingly, no changes were necessary to apply this
protocol to more oxidatively-sensitive α-primary benzylamines,
and the corresponding o-biaryls could be prepared without
concomitant oxidation of the benzylamine (2l and 2m). Even α-
secondary benzylamines, which could be expected to undergo
β-hydride elimination to generate imines during the reaction,42
gave the unoxidized amine products in excellent yields (2n –
2p). It is noteworthy that in cases where the yields are moderate,
a significant part of the mass balance is actually unreacted
amine, suggesting that the catalyst eventually dies in the
reaction before all of the substrate is consumed. We tried
circumventing this by opening the reaction vessels mid-reaction
and adding a second portion of catalyst and re-pressurizing, but
found this did not have an appreciable benefit on the reaction.
The difference in polarity between starting materials and
products is also low, and in some examples the yield is
hampered by the inability to achieve complete baseline
separation during purification by column chromatography.
Table 3. Primary Benzylamine Scope of the γ-C(sp2)‒H
Arylation with Aryl Halides.
I
NH2
R1
R3
NH2
R3
Pd(OAc)2 (10 mol%)
AgTFA (2.0 equiv.)
R2
R1
+
R2
CO2, H2O
HFIP/AcOH
CO2Et
CO2Et
2a-p
Based on our previous success applying carbon dioxide to
the functionalization of secondary amines, we considered that it
might help prevent oxidation problems.74 The optimized
conditions were found to indeed promote the C‒H arylation of
secondary benzylamines while preventing deleterious oxidation
pathways. Substrates bearing linear (Table 4, 3a) and branched
(3b – 3d) chains added to the benzylamine were able to
participate in the reaction. Amines bearing various carbocycles
(3e – 3g) were also viable under the standard reaction
conditions. Aryl groups could be added to the benzylamine via
either a β (3h) or γ (3i) linkage without degraded
regioselectivity for arylation of the γ-C(sp2)‒H bond. We were
delighted to find that unsaturated (3j) as well as saturated (3k –
3o) heterocycles appended to the benzylamine could also
survive the reaction conditions, although it is worth noting that
appending an N-methylpyrrole moiety to the benzylamine
failed to give product under these conditions, presumably due
to its increased nucleophilicity. The presence of two potentially
competitive γ-C(sp2)–H bonds on 3j made us wonder if
activation on a five-membered heterocycle might be possible.75
However, when the reaction was performed on N,N-bis-(2-
furylmethyl)amine under the standard conditions nearly
F
NH2
Ar
F
NH2
Ar
F
NH2
nBu
F
NH2
nHex
Ar
Ar
2a, 72%
F
2b, 70%
2c, 63%
Cl
2d, 59%
Me
NH2
Ar
Cl
NH2
NH2
NH2
Ar
Ar
Ar
2e, 66%
MeO
2f, 61%
F
2g, 75%
2h, 82%
F
F
NH2
NH2
F
NH2
NH2
Ph
Ar
Ar
Ar
Ar
2i, 77%
2k, 71%
Cl
2l, 70%
2j, 68%
F
NH2
Ar
NH2
NH2
NH2
MeO
Br
Ar
Ar
Ar
2m, 68%
2o, 84%
2p, 80%
2n, 81%
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Page 4 of 11
O
O
quantitative recovery of the starting amine was observed
HN
I
1
2
(Scheme 1). At this point it is unclear whether the reaction fails
to functionalize the heterocycle for an electronic reason or
because of the difference in ring size and shape.
Pd(OAc)2 (10 mol%)
AgTFA (2.0 equiv.)
O
HN
+
3
4
Table 4. Secondary Benzylamine Scope of the γ-C(sp2)‒H
O
CO2, H2O
HFIP/AcOH
CO2Et
CO2Et
~Quantitative
Recovery of Amine SM
Arylation with Aryl Halides.
5
6
7
8
0.15 mmol
3 equiv.
R1
R1
Ar1 = 4-Ester
Table 5. Scope of the Di-γ-C(sp2)‒H Arylation of Sterically-
Accessible Benzylamines.
HN
Ar2 = 2-Ester
I
R3
R1
R2
HN
Pd(OAc)2 (10 mol%)
AgTFA (2.0 equiv.)
9
R3
+
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
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29
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40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
R3
CO2, H2O
I
NH2
NH2
R1
HFIP/AcOH
CO2Et
F
3a-o
Pd(OAc)2 (10 mol%)
AgTFA (2.0 equiv.)
CO2Et
R1
+
R2
R2
F
F
CO2, H2O
HFIP/AcOH
nBu
R3
R3
N
N
N
H
4a 4j
-
H
H
Ar1
3a, 71%
Ar1
3b, 67%
Ar1
NO2
CO2Et
CO2Et
3c, 71%
Cl
F
MeO
iPr
ad
Cy
N
H
N
N
NH2
NH2
H
H
NH2
Ar1
3d, 51%
Ar1
3e, 57%
Cl
F
Ar1
3f, 72%
O
O
Ph
NO2
CO2Et
MeO
Cy
CO2Et
F3C
N
H
Ar1
4a, 68%
4b,70%, >96% es
4c, 47%
N
H
2
>96% ee
Ar1
3h, 57%
CO2Et
N
H
3g, 84%
CO2Et
NH2
Ar1
3i, 66%
NH2
O
O
O
F
F
F3C
N
H
Ar1
N
N
CO2Et
H
H
Ar1
3k, 64%
Ar1
3l, 86%
3j, 43%
CO2Et
4d, 61%
4e, 72%
CO2Et
O
O
O
NO2
CO2Et
Ph
F3C
O2N
N
H
N
N
H
H
Ar2
3m, 88%
Ar1
3n, 52%
Ar1
3o, 60%
NH2
NH2
NH2
F
Reactions set-up using amine (0.15 mmol), halide (0.45 mmol),
Pd(OAc)2 (0.015 mmol), AgTFA (0.30 mmol), CO2 (~0.75 mmol),
H2O (0.60 mmol), 1 mL of HFIP/AcOH (7:3), followed by running
at 100 ºC for 12-15h. Reactions were run in duplicate and the
average yield reported.
CO2Et
CO2Et
Ph
4g, 71%
4h, 62%
4f, 81%, >96% es
>96% ee
Unsurprisingly, we found that in the absence of a
substituent at the 2 or 3-position, diarylation products were
afforded with great selectivity when excess aryl halide was used
(Table 5), although dropping the ratio to less than six
equivalents of halide led to a mixture of mono and di-arylation
products. The rationale for this is that although the reactive C‒H
bond is not forced towards the catalyst during the initial
reaction, after arylation the aromatic ring will adopt a
conformation where the second o-C‒H bond becomes more
accessible, leading to faster C–H activation of the
monosubstituted benzylamines compared to the unsubstituted
starting material.
CO2Et
NH2
NH2
CO2Me
CO2Et
4i, 66%
4j, 68%
Reactions set-up using amine (0.15 mmol), halide (0.75 mmol),
Pd(OAc)2 (0.015 mmol), AgTFA (0.30 mmol), CO2 (~0.75 mmol),
H2O (0.60 mmol), 1 mL of HFIP/AcOH (7:3), followed by running
at 100 ºC for 12-15h. Reactions were run in duplicate and the
average yield reported. The ee was determined by preparation of
Scheme 1. Attempted Arylation of N,N-Bis-(2-
furfurylmethyl)amine.
1
the Mosher amides and comparison of the diastereomers by H
NMR.
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The m-terphenyl products could be achieved with α-
NH2
R1
I
NH2
1
2
3
4
5
6
7
8
tertiary and secondary benzylamines (4a – 4c). Notably, using
an enantioenriched starting material, the configuration was
retained with no erosion in the enantiomeric excess (ee) (4b)
(determined by preparing the Mosher amide, see SI for details).
α-Primary benzylamines are also viable substrates in the
reaction (4d and 4e). By using 4-phenyl iodobenzene as the
electrophile, it is even possible to rapidly access a highly
conjugated m-pentaphenyl with an amine moiety (4f), again
with no erosion in ee. Substrates containing both benzylic and
homobenzylic positions also still gave complete selective for
diarylation of solely the benzylic ring (4g and 4h). Given the
ability to potentially synthesize highly conjugated substrates,
we next targeted a bis-fluorene (4i), although this was not
particularly emissive. Finally, use of a β-phenylalanine ester
also led to the diarylation products in good yield with no
observable α-arylation (4j) of either the amine or ester carbonyl.
Pd(OAc)2 (10 mol%)
AgTFA (2.0 equiv.)
R2
+
R1
R2
CO2, H2O
HFIP/AcOH
CO2Et
5a g
-
CO2Et
NH2
O
NEt2
NH2
O
NPr2
NH2
O
O
OMe
NH2
NH2
Ar
Ar
Ar
Ar
9
5b, 65%
50% es
50% ee
5c, 57%
61% es
60% ee
5d, 47%a
<4% es
<4% ee
5a, 69%
15% es,
15% ee
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
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39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
OEt
OH
NH2
OAc
NH2
O
P
OEt
NH2
Ar
Ar
Ar
While exploring the diarylation of benzylamines, we
discovered an interesting outlier: subjecting methyl
phenylglycine to the reaction conditions led to selective
monoarylation (Table 6, 5a), even without utilizing the blocking
method. We assumed there might be a chelation effect from the
pendant ester that leads to the unusual selectivity. Encouraged
by this result, we explored a number of other substrates with
chelating groups: replacing the ester with an amide (5b – 5d)
still led to monoarylation when only three equivalents of aryl
halide were utilized. The relatively acidic α-proton in substrates
5a – 5c led to significant erosion of ee during the reaction.
Notably, the free amide required a slight modification to the
conditions (5d), and gave the almost completely racemized
product after the reaction. While the presence of a β-carbonyl
was clearly effective in achieving monoarylation, we wondered
if other groups might facilitate this selectivity, and found that
placing an alcohol β to the amine could also prevent diarylation
(5e). Protection of the alcohol as an ester was also effective in
the selective monoarylation (5f). The es for 5e and 5f was much
higher than for the more acidic substrates, at 90% and 88%
respectively. To our surprise, even an α-phosphonate ester
could be used to achieve selective monoarylation (5g).
5f, 47%
88% es
86% ee
5e, 61%
90% es
88% ee
5g, 52%
Reactions set-up using amine (0.15 mmol), halide (0.45 mmol),
Pd(OAc)2 (0.015 mmol), AgTFA (0.30 mmol), CO2 (~0.75 mmol),
H2O (0.60 mmol), 1 mL of HFIP/AcOH (7:3), followed by running
at 100 ºC for 12-15h. Reactions were run in duplicate and the
average yield reported. The ee was determined by preparation of
1
the Mosher amides and comparison of the diastereomers by H
NMR.
To demonstrate the synthetic utility for this chemistry, we
also wanted to show that the reactions could be performed on
larger scale (Scheme 2). Performing the reaction at 100 times
the scale (from 0.15 mmol to 15 mmol) gave a similar yield
(Scheme 2a). We wondered if higher than 1 atmosphere of CO2
pressure was still needed at this scale, and so we performed the
reaction under standard Schlenk conditions with 1 atmosphere
of CO2. Under these conditions the yield was less than half
(Scheme 2b), showing that the pressure of CO2 is critical for
the optimal functioning of this chemistry.
Table 6. Scope of the Selective Mono-γ-C(sp2)‒H Arylation
of Sterically-Accessible Benzylamines.
Scheme 2. Scale-up Experiments.
a) Sealed Tube
I
F
F
NH2
Pd(OAc)2 (10 mol%)
AgTFA (2.0 equiv.)
NH2
+
CO2, H2O
HFIP/AcOH
CO2Et
CO2Et
15 mmol
Scale
2l, 71%
F
b) Schlenk Line
NH2
I
F
Pd(OAc)2 (10 mol%)
AgTFA (2.0 equiv.)
NH2
+
CO2, H2O
HFIP/AcOH
CO2Et
CO2Et
15 mmol
Scale
2l, 30%
Reactions set-up using amine (15.0 mmol), halide (45.0 mmol),
Pd(OAc)2 (1.50 mmol), AgTFA (30.0 mmol), CO2 (~0.75 mmol),
H2O (0.60 mmol), 1 mL of HFIP/AcOH (7:3), followed by running
at 100 ºC for 12-15h. Reactions were run in duplicate and the
average yield reported.
After gaining a better understanding of the substrate
scope, our next goal was to demonstrate the utility of the
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reaction to a known synthetic target, and so we applied this C–
separation during purification (see SI for details).32, 77 Amine 6
can then be treated with the corresponding epoxide and cyclized
to give Anacetrapib using a known procedure.78
1
2
3
4
5
6
7
8
H arylation approach to a key step in the synthesis of
Anacetrapib, a CETP inhibitor that until recently was being
investigated by Merck (Scheme 3).76 The requisite aryl halide
can be synthesized in three steps, and although ortho-
substituted aryl halides are generally poor substrates for C‒H
arylation reactions, by using AgOTf as the additive, the o-biaryl
can be achieved in 42%. The use of Ag additives with relatively
poorly coordinating counterions for C‒H arylation with o-
substituted iodoarenes appears to be a relatively reliable
approach for using these more sterically-hindered aryl halide
substrates, although in the present study other halides (2-
fluoroiodobenzene and 2-iodoanisole) gave much poorer yields
due both to lower conversion and difficulty achieving baseline
Having demonstrated the synthetic utility of our approach,
our final goal was to try to better understand the mechanism of
this C‒H arylation. Control reactions indicated a vital role for
CO2 during the reaction (Table 1, Entry 18), and we therefore
wondered whether or not substoichiometric carbon dioxide was
sufficient to catalyze the reaction (Figure 2a). The ammonium
carbamate salt 7 was prepared, which would introduce only a
half equivalent of carbon dioxide into the reaction. This gave
57% yield in the arylation reaction (in the absence of additional
CO2), suggesting that an excess of CO2 was not neccessary for
the reaction to proceed. We were also interested in looking at
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Scheme 3. Total Synthesis of rac-Anacetrapib via γ-C(sp2)‒H Arylation of a Benzylamine Precursor.
F3C
Me
OMe
F3C
Pd(OAc)2 (10 mol%)
AgOTf (2.0 eq.)
NH2
F3C
I
F
F3C
F
NH2
CO2 (5 eq.)
H2O (4.0 equiv.)
HFIP
+
N
F
MeO
iPr
MeO
6, 42%
iPr
O
Commercially
Available
Me
Me
O
100 oC, 14h
61% Over 3 Steps
F3C
Anacetrabip
the kinetic isotope effect, and considered that if the C–H
activation step happened to be reversible, this would also serve
as
capacity. One possibility would be that Pd-bisamine complexes
that might be present are disrupted by CO2, but these are
destabilized under acidic conditions, and so we didn’t consider
80
this to be a likely role.77,
PdII-benzylamine systems give
a facile way to install deuterium to perform these studies. Using
both Daugulis’ conditions42 as well as our own in the presence
of fully deuterated solvents, however, no deuteration was
observed (Figure 2b). We instead prepared the analogous
deuterated carboxylic acid and then converted it into the amine
substrate 8 (see SI for details). The rate of reaction was
compared between the proteo and deutero substrates under our
conditions, and was found to exhibit a kinetic isotope effect of
~1.5 (Figure 2c), suggesting that C‒H activation is unlikely to
be rate determining, in contrast to our previous example of CO2-
mediated C‒H activation.66
bridged dinuclear complexes before C–H activation, followed
by a slow and then a relatively facile C–H activation to form
cyclometalated dimers.81-84 These cyclometalated dimers can be
disrupted by additional ligands,85 but in terms of catalytic
reactions (such as ours) without additional ligands, we
anticipate that these dimers may serve as a thermodynamic sink,
and are the cause for the high reaction temperatures that have
previously been required for turnover. Because of this we
postulated that CO2 may be disrupting these dimers, and
prepared complex 979, 81 to assess whether this was a reasonable
hypothesis. To our surprise, when 9 was subjected to the
standard reaction conditions, no desired arylation was observed
(Figure 2d). This suggests that CO2 may actually be preventing
the formation of these dimers rather than disrupting them after
formation, though further work is needed to better understand
the exact role of CO2 in this process.
We next began to consider the exact role of CO2 in this
process. Cyclopalladated intermediates of primary and
secondary benzylamines have been made before under
relatively mild conditions without the need for an additional
directing group.79 This left us to consider whether or not CO2
was acting as a directing group, or serving in a separate
Figure 2. Experimental Mechanistic Studies on the CO2-Mediated C–H Arylation of Benzylamines.
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a) Substoichiometric CO2 Loading
I
NH2
1
2
Pd(OAc)2 (10 mol%)
MeO
AgTFA (2.0 equiv.)
MeO
NHCO2
3
4
5
6
7
8
9
H3N
+
H2O (4.0 equiv.)
HFIP/AcOH (0.7/0.3)
100 oC, 12h
OMe
CO2Et
7
57%
CO2Et
F
b) Deuterated Solvent Study
F
F
F
Pd(OAc)2 (10 mol%)
AgTFA (2.0 equiv.)
Pd(OAc)2 (5 mol%)
AgOAc (2.0 equiv.)
NH2
NH2
NH2
98%
NH2
TFA-d (5.0 equiv.)
CO2 (5.0 equiv.)
D2O (4.0 equiv.)
AcOD
130 oC, 2.5h
96%
Daugulis
Conditions
No Substrate
Deuteration
100 oC, 12h
No Substrate
Deuteration
Present
Conditions
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
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37
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39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
c) Kinetic Isotope Effect
D 67%
D 67%
I
Pd(OAc)2 (10 mol%)
AgTFA (2.0 equiv.)
F3C
NH2
F3C
+
NH2
CO2 (5.0 equiv.)
H2O (4.0 equiv.)
KIE = 1.5
D
97%
HFIP/AcOH (0.7/0.3)
8
CO2Et
NH2
CO2Et
100 o
C
d) C-H Arylation from Stoichiometric Dimers
Ar
O
I
AgTFA (2.0 equiv.)
Pd
O
N
+
No Product Observed
H
H22
CO2 (5.0 equiv.)
H2O (4.0 equiv.)
HFIP/AcOH (0.7/0.3)
100 oC, 14h
N
Ar
O
Pd
9
O
CO2Et
e) CO2 Deinsertion Experiment
I
Pd(OAc)2 (10 mol%)
AgTFA (2.0 equiv.)
+
NH2
NH2
CO2 (5.0 equiv.)
H2O (4.0 equiv.)
HFIP/AcOH (0.7/0.3)
100 oC, 12h
CO2H
10
CO2Et
71%
While CO2 was found to be advantageous, we found that
By appending chelating groups β to the amine, we have even
shown how unblocked benzylamine substrates can be
selectively monoarylated due to a putative chelate effect.
Further efforts are underway in our lab to better understand the
role of CO2 in these reactions, as well as to expand the list of
functional groups that can be installed utilizing this approach to
C–H activation.
going in excess of between five and ten equivalents during the
reaction actually led to decreased yields. We wondered whether
or not there was any possibility of competitive C–H
carboxylation occurring, and to probe this we prepared the
ortho-carboxybenzylamine 10. When 10 was subjected to the
reaction conditions, it was completely degraded to the
unsubstituted benzylamine (Figure 2e), yet no concomitant
arylation product was observed. Under the reaction conditions
there is superstoichiometric silver present, and this has
previously been shown to lead to decarboxylation of aryl
carboxylic acids.86 Presumably the lack of subsequent C–H
arylation comes from deactivation (possibly by reduction from
Ag0 formed in situ) of the PdII catalyst. It stands to reason in our
catalytic reaction that if any C–H carboxylation were to occur
at higher CO2 loading, it would then lead to loss of PdII catalyst,
thus lowering the rate. Although further studies are needed, we
feel that this deactivation scenario fits the data. The important
takeaway is that proper screening of CO2 is important for these
reactions, and a would-be practitioner should not assume that
more CO2 will always lead to a better result.
ASSOCIATED CONTENT
Supporting Information. Details related to synthesis of starting
materials, reaction optimization, and products, as well as
characterization for all new compounds including 1H and 13C NMR
as well as mass spectrometric data, can be found in the Supporting
Information. This material is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
* Michael C. Young: michael.young8@utoledo.edu
Author Contributions
■ CONCLUSION
The manuscript was written through contributions of all authors. /
All authors have given approval to the final version of the
manuscript.
In summary, we have demonstrated how carbon dioxide
can be used to facilitate ortho-arylation of benzylamine
substrates under milder conditions than the free amine alone42
or by using an aldehyde-based transient directing group
approach.32 This allows a broad substrate scope of primary
benzylamines, while simultaneously allowing oxidatively-
sensitive secondary benzylamines to participate in the reaction.
Funding Sources
The authors wish to acknowledge start-up funding from the
University of Toledo, as well as a grant from the ACS Herman
Frasch Foundation (830-HF17) in partial support of this work.
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Page 8 of 11
15.
Cabrera, P. J.; Lee, M.; Sanford, M. S., Second-
Conflicts of Interest
1
2
3
4
5
6
7
8
Generation Palladium Catalyst System for Transannular C–H
Functionalization of Azabicycloalkanes. J. Am. Chem. Soc. 2018,
140, 5599-5606.
The work in this manuscript is covered by US Patent
Application 16/223,467.
16.
Smalley, A. P.; Cuthbertson, J. D.; Gaunt, M. J.,
ACKNOWLEDGMENT
Palladium-Catalyzed Enantioselective C–H Activation of Aliphatic
Amines Using Chiral Anionic BINOL-Phosphoric Acid Ligands. J.
Am. Chem. Soc. 2017, 139, 1412-1415.
Dedicated to the memory of Prof. Dean Giolando (1957-2019). Mr.
Justin Maxwell and Mr. Daniel Liu are acknowledged for checking
the reproducibility of this chemistry. Ms. Krishani Rajanayake and
Mr. Govind-Sharma Shyam Sundar are acknowledged for
collecting high resolution ESI-MS data at The University of
Toledo. Dr. Ian Riddington and Dr. Kristin Blake are
acknowledged for collecting high resolution ESI-MS data at the
Mass Spectrometry Facility, Dept. of Chemistry, University of
Texas at Austin. Prof. Jianglong Zhu of The University of Toledo
is acknowledged for useful discussions. Finally, we wish to
acknowledge ChemRxiv for allowing this manuscript to be posted
as a pre-print (7138088).
17.
Topczewski, J. J.; Cabrera, P. J.; Saper, N. I.; Sanford,
M. S., Palladium-catalysed transannular C–H functionalization of
alicyclic amines. Nature 2016, 531, 220.
9
18.
Corbin, J. R.; Schomaker, J. M., Tunable differentiation
10
11
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43
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55
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57
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59
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of tertiary C–H bonds in intramolecular transition metal-catalyzed
nitrene transfer reactions. Chem. Commun. 2017, 53, 4346-4349.
19.
Du Bois, J., Rhodium-Catalyzed C–H Amination. An
Enabling Method for Chemical Synthesis. Org. Proc. Res. Dev.
2011, 15, 758-762.
20.
Mbofana, C. T.; Chong, E.; Lawniczak, J.; Sanford, M.
S., Iron-Catalyzed Oxyfunctionalization of Aliphatic Amines at
Remote Benzylic C–H Sites. Org. Lett. 2016, 18, 4258-4261.
REFERENCES
21.
Beck, E. M.; Stepan, A. F.; Webb, D., Chapter 8 C–H
1.
Froidevaux, V.; Negrell, C.; Caillol, S.; Pascault, J.-P.;
Activation Approaches to Molecules. In Synthetic Methods in Drug
Discovery: Volume 1, The Royal Society of Chemistry: 2016; Vol.
1, pp 274-383.
Boutevin, B., Biobased Amines: From Synthesis to Polymers;
Present and Future. Chem. Rev. 2016, 116, 14181-14224.
2.
Guo, X.; Facchetti, A.; Marks, T. J., Imide- and Amide-
22.
Gulia, N.; Daugulis, O., Palladium-Catalyzed Pyrazole-
Functionalized Polymer Semiconductors. Chem. Rev. 2014, 114,
8943-9021.
Directed sp3 C−H Bond Arylation for the Synthesis of β-
Phenethylamines. Angew. Chem. Int. Ed. 2017, 56, 3630-3634.
3.
Kobayashi, S.; Makino, A., Enzymatic Polymer
23.
He, G.; Wang, B.; Nack, W. A.; Chen, G., Syntheses
Synthesis: An Opportunity for Green Polymer Chemistry. Chem.
Rev. 2009, 109, 5288-5353.
and Transformations of α-Amino Acids via Palladium-Catalyzed
Auxiliary-Directed sp3 C–H Functionalization. Acc. Chem. Res.
2016, 49, 635-645.
4.
Allred, T. K.; Manoni, F.; Harran, P. G., Exploring the
Boundaries of “Practical”: De Novo Syntheses of Complex Natural
Product-Based Drug Candidates. Chem. Rev. 2017, 117, 11994-
12051.
24.
Huang, Z.; Wang, C.; Dong, G., A Hydrazone-Based
exo-Directing-Group Strategy for βꢀC−H Oxidation of Aliphatic
Amines. Angew. Chem. Int. Ed. 2016, 55, 5299-5303.
5.
Manallack, D. T.; Prankerd, R. J.; Yuriev, E.; Oprea, T.
25.
Noisier, A. F. M.; Brimble, M. A., C–H
I.; Chalmers, D. K., The significance of acid/base properties in drug
discovery. Chem. Soc. Rev. 2013, 42, 485-496.
Functionalization in the Synthesis of Amino Acids and Peptides.
Chem. Rev. 2014, 114, 8775-8806.
6.
Brandänge, S.; Rodriguez, B., A Convenient Route to 3-
26.
Shi, H.; Herron, A. N.; Shao, Y.; Shao, Q.; Yu, J.-Q.,
Pyrroline Utilizing the Delépine Reaction. Synthesis 1988, 1988,
347-348.
Enantioselective remote meta-C–H arylation and alkylation via a
chiral transient mediator. Nature 2018, 558, 581-585.
7.
Dangerfield, E. M.; Plunkett, C. H.; Win-Mason, A. L.;
27.
Zaitsev, V. G.; Shabashov, D.; Daugulis, O., Highly
Stocker, B. L.; Timmer, M. S. M., Protecting-Group-Free Synthesis
of Amines: Synthesis of Primary Amines from Aldehydes via
Reductive Amination. J. Org. Chem. 2010, 75, 5470-5477.
Regioselective Arylation of sp3 C−H Bonds Catalyzed by
Palladium Acetate. J. Am. Chem. Soc. 2005, 127, 13154-13155.
28.
Chuentragool, P.; Parasram, M.; Shi, Y.; Gevorgyan, V.,
8.
Le, Z.-G.; Chen, Z.-C.; Hu, Y.; Zheng, Q.-G., Organic
General, Mild, and Selective Method for Desaturation of Aliphatic
Amines. J. Am. Chem. Soc. 2018, 140, 2465-2468.
Reactions in Ionic liquids: N-Alkylation of Phthalimide and
Several Nitrogen Heterocycles. Synthesis 2004, 2004, 208-212.
29.
Maiti, D.; Paton, R. S.; Guin, S.; Dolui, P.; Zhang, X.;
9.
Dong, Z.; Dong, G., Ortho vs Ipso: Site-Selective Pd and
Paul, S.; Singh, V. K.; Pradhan, S.; Chandrashekar, H. B.; S, A.
S., Iterative Arylation of Amino Acids and Aliphatic Amines via
δ‐C(sp3)−H Activation: Experimental and Computational
Exploration. Angew. Chem. Int. Ed. 2019, 58, 5633-5638.
Norbornene-Catalyzed Arene C–H Amination Using Aryl Halides.
J. Am. Chem. Soc. 2013, 135, 18350-18353.
10.
Nagano, T.; Kobayashi, S., Palladium-Catalyzed Allylic
Amination Using Aqueous Ammonia for the Synthesis of Primary
Amines. J. Am. Chem. Soc. 2009, 131, 4200-4201.
30.
Albert, J.; Ariza, X.; Calvet, T.; Font-Bardia, M.;
Garcia, J.; Granell, J.; Lamela, A.; López, B.; Martinez, M.;
Ortega, L.; Rodriguez, A.; Santos, D., NH2 As a Directing Group:
From the Cyclopalladation of Amino Esters to the Preparation of
Benzolactams by Palladium(II)-Catalyzed Carbonylation of N-
Unprotected Arylethylamines. Organometallics 2013, 32, 649-659.
11.
Turnpenny, B. W.; Chemler, S. R., Copper-catalyzed
alkene diamination: synthesis of chiral 2-aminomethyl indolines
and pyrrolidines. Chem. Sci. 2014, 5, 1786-1793.
12.
Wu, F.; Stewart, S.; Ariyarathna, J. P.; Li, W., Aerobic
Copper-Catalyzed Alkene Oxyamination for Amino Lactone
Synthesis. ACS Catal. 2018, 8, 1921-1925.
31.
Haffemayer, B.; Gulias, M.; Gaunt, M. J., Amine
directed Pd(ii)-catalyzed C–H bond functionalization under
ambient conditions. Chem. Sci. 2011, 2, 312-315.
13.
Simonetti, M.; Cannas, D. M.; Just-Baringo, X.;
Vitorica-Yrezabal, I. J.; Larrosa, I., Cyclometallated ruthenium
catalyst enables late-stage directed arylation of pharmaceuticals.
Nature Chem. 2018, 10, 724-731.
32.
Lin, H.; Wang, C.; Bannister, T. D.; Kamenecka, T. M.,
Site-Selective γ-C(sp3)−H and γ-C(sp2)−H Arylation of Free
Amino Esters Promoted by a Catalytic Transient Directing Group.
Chem. Eur. J. 2018, 24, 9535-9541.
14.
Antermite, D.; Affron, D. P.; Bull, J. A., Regio- and
Stereoselective Palladium-Catalyzed C(sp3)–H Arylation of
Pyrrolidines and Piperidines with C(3) Directing Groups. Org. Lett.
2018, 20, 3948-3952.
33.
Xin, Z.; Peng, H.; Zhang, A.; Talreja, T.; Kumaravel,
G.; Xu, L.; Rohde, E.; Jung, M.-y.; Shackett, M. N.; Kocisko,
D.; Chollate, S.; Dunah, A. W.; Snodgrass-Belt, P. A.; Moore
ACS Paragon Plus Environment

Page 9 of 11
Journal of the American Chemical Society
Arnold, H.; Taveras, A. G.; Rhodes, K. J.; Scannevin, R. H.,
Discovery of 4-aminomethylphenylacetic acids as γ-secretase
modulators via a scaffold design approach. Bioorg. Med. Chem.
Lett. 2011, 21, 7277-7280.
51.
Gandeepan, P.; Ackermann, L., Transient Directing
1
2
3
4
5
6
Groups for Transformative C–H Activation by Synergistic Metal
Catalysis. Chem 2018, 4, 199-222.
52.
Methylation and Fluorination of Benzaldehydes Using Orthanilic
Acids as Transient Directing Groups. J. Am. Chem. Soc. 2018, 140,
2789-2792.
Chen, X.-Y.; Sorensen, E. J., Pd-Catalyzed, ortho C–H
34.
Syvitski, R. T.; Borissow, C. N.; Graham, C. L.;
Jakeman, D. L., Ring-Opening Dynamics of Jadomycin A and B
and Dalomycin T. Org. Lett. 2006, 8, 697-700.
35.
Tomioka, K.; Kubota, Y.; Kawasaki, H.; Koga, K.,
53.
Yang, K.; Li, Q.; Liu, Y.; Li, G.; Ge, H., Catalytic C–
7
8
9
Design, synthesis, and antitumor activity of steganacin aza-
analogues. Tetrahedron Lett. 1989, 30, 2949-2952.
H Arylation of Aliphatic Aldehydes Enabled by a Transient
Ligand. J. Am. Chem. Soc. 2016, 138, 12775-12778.
36.
Paull, D. H.; Fang, C.; Donald, J. R.; Pansick, A. D.;
54.
Zhang, F.-L.; Hong, K.; Li, T.-J.; Park, H.; Yu, J.-Q.,
Martin, S. F., Bifunctional Catalyst Promotes Highly
Enantioselective Bromolactonizations To Generate Stereogenic C–
Br Bonds. J. Am. Chem. Soc. 2012, 134, 11128-11131.
Functionalization of C(sp3)–H bonds using a transient directing
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
group. Science 2016, 351, 252-256.
55.
with simple olefins via dual activation. Science 2014, 345, 68-72.
56. Park, H.; Verma, P.; Hong, K.; Yu, J.-Q., Controlling
Mo, F.; Dong, G., Regioselective ketone α-alkylation
37.
Xu, W.; Arieno, M.; Löw, H.; Huang, K.; Xie, X.;
Cruchter, T.; Ma, Q.; Xi, J.; Huang, B.; Wiest, O.; Gong, L.;
Meggers, E., Metal-Templated Design: Enantioselective
Hydrogen-Bond-Driven Catalysis Requiring Only Parts-per-
Million Catalyst Loading. J. Am. Chem. Soc. 2016, 138, 8774-
8780.
Pd(IV) reductive elimination pathways enables Pd(II)-catalysed
enantioselective C(sp3)−H fluorination. Nature Chem. 2018, 10,
755-762.
57.
Xia, Y.; Lu, G.; Liu, P.; Dong, G., Catalytic activation
38.
Hoggard, L. R.; Zhang, Y.; Zhang, M.; Panic, V.;
of carbon–carbon bonds in cyclopentanones. Nature 2016, 539,
546.
Wisniewski, J. A.; Ji, H., Rational Design of Selective Small-
Molecule Inhibitors for β-Catenin/B-Cell Lymphoma 9 Protein–
Protein Interactions. J. Am. Chem. Soc. 2015, 137, 12249-12260.
58.
Liu, Y.; Ge, H., Site-selective C–H arylation of primary
aliphatic amines enabled by a catalytic transient directing group.
Nature Chem. 2016, 9, 26.
39.
Boudreault, P.-L.; Cardinal, S.; Voyer, N., Efficient
Preparation of 2-Aminomethylbiphenyls via Suzuki-Miyaura
Reactions. Synlett 2010, 2010, 2449-2452.
59.
Wu, Y.; Chen, Y.-Q.; Liu, T.; Eastgate, M. D.; Yu, J.-
Q., Pd-Catalyzed γ-C(sp3)–H Arylation of Free Amines Using a
Transient Directing Group. J. Am. Chem. Soc. 2016, 138, 14554-
14557.
40.
Zhu, J.; Ye, Y.; Ning, M.; Mándi, A.; Feng, Y.; Zou,
Q.; Kurtán, T.; Leng, Y.; Shen, J., Design, Synthesis, and
Structure–Activity Relationships of 3,4,5-Trisubstituted 4,5-
Dihydro-1,2,4-oxadiazoles as TGR5 Agonists. ChemMedChem
2013, 8, 1210-1223.
60.
Xu, Y.; Young, M. C.; Wang, C.; Magness, D. M.;
Dong, G., Catalytic C(sp3)−H Arylation of Free Primary Amines
with an exo Directing Group Generated InꢀSitu. Angew. Chem. Int.
Ed. 2016, 55, 9084-9087.
41.
Wang, X.; Leow, D.; Yu, J.-Q., Pd(II)-Catalyzed para-
Selective C–H Arylation of Monosubstituted Arenes. J. Am. Chem.
Soc. 2011, 133, 13864-13867.
61.
Yada, A.; Liao, W.; Sato, Y.; Murakami, M.,
Buttressing Salicylaldehydes: A Multipurpose Directing Group for
C(sp3)−H Bond Activation. Angew. Chem. Int. Ed. 2017, 56, 1073-
1076.
42.
Ortho-Arylation of Benzylamines. Org. Lett. 2006, 8, 5211-5213.
43. Feng, R.; Yao, J.; Liang, Z.; Liu, Z.; Zhang, Y., Cu(II)-
Lazareva, A.; Daugulis, O., Direct Palladium-Catalyzed
62.
St John-Campbell, S.; Ou, A. K.; Bull, J. A., Palladium
Promoted Palladium-Catalyzed C–H Ortho-Arylation of N,N-
Dimethylbenzylamines. J. Org. Chem. 2013, 78, 3688-3696.
Catalyzed C(sp3)–H Arylation of Primary Amines Using a
Catalytic Alkyl Acetal to Form a Transient Directing Group. Chem.
Eur. J. 2018, 24, 17838-17843.
44.
Tan, P. W.; Haughey, M.; Dixon, D. J., Palladium(ii)-
catalysed ortho-arylation of N-benzylpiperidines. Chem. Commun.
2015, 51, 4406-4409.
63.
Chen, Y.-Q.; Wang, Z.; Wu, Y.; Wisniewski, S. R.;
Qiao, J. X.; Ewing, W. R.; Eastgate, M. D.; Yu, J.-Q., Overcoming
the Limitations of γ- and δ-C–H Arylation of Amines through
Ligand Development. J. Am. Chem. Soc. 2018, 140, 17884-17894.
45.
Li, H.; Cai, G.-X.; Shi, Z.-J., LiCl-Promoted Pd(ii)-
catalyzed ortho carbonylation of N,N-dimethylbenzylamines.
Dalton Trans. 2010, 39, 10442-10446.
64.
Luo, J.; Preciado, S.; Larrosa, I., Salicylic acids as
46.
Cai, G.; Fu, Y.; Li, Y.; Wan, X.; Shi, Z., Indirect ortho
readily available starting materials for the synthesis of meta-
substituted biaryls. Chem. Commun. 2015, 51, 3127-3130.
Functionalization of Substituted Toluenes through ortho
Olefination of N,N-Dimethylbenzylamines Tuned by the Acidity
of Reaction Conditions. J. Am. Chem. Soc. 2007, 129, 7666-7673.
65.
Johnston, A. J. S.; Ling, K. B.; Sale, D.; Lebrasseur, N.;
Larrosa, I., Direct ortho-Arylation of Pyridinecarboxylic Acids:
Overcoming the Deactivating Effect of sp2-Nitrogen. Org. Lett.
2016, 18, 6094-6097.
47.
Dong, Z.; Wang, J.; Dong, G., Simple Amine-Directed
Meta-Selective C–H Arylation via Pd/Norbornene Catalysis. J. Am.
Chem. Soc. 2015, 137, 5887-5890.
66.
Kapoor, M.; Liu, D.; Young, M. C., Carbon Dioxide-
48.
Zhang, C.; Ding, Y.; Gao, Y.; Li, S.; Li, G., Palladium-
Mediated C(sp3)–H Arylation of Amine Substrates. J. Am. Chem.
Soc. 2018, 140, 6818-6822.
Catalyzed Direct C–H Carbonylation of Free Primary
Benzylamines: A Synthesis of Benzolactams. Org. Lett. 2018, 20,
2595-2598.
67.
Kapoor, M.; Chand-Thakuri, P.; Maxwell, J. M.; Young,
M. C., Achieving Moderate Pressures in Sealed Vessels Using Dry
Ice As a Solid CO2 Source. J. Vis. Exp. 2018, e58281.
49.
Lin, H.; Pan, X.; Barsamian, A. L.; Kamenecka, T. M.;
Bannister, T. D., Native Directed Site-Selective δ-C(sp3)-H and δ-
C(sp2)-H Arylation of Primary Amines. ACS Catal. 2019, DOI:
10.1021/acscatal.8b04927.
68.
Hogg, K. F.; Trowbridge, A.; Alvarez-Pérez, A.; Gaunt,
M. J., The α-tertiary amine motif drives remarkable selectivity for
Pd-catalyzed carbonylation of β-methylene C–H bonds. Chem. Sci.
2017, 8, 8198-8203.
50.
Pramanick, P. K.; Zhou, Z.; Hou, Z.-L.; Yao, B., Free
Amino Group-Directed γ-C(sp3)–H Arylation of α-Amino Esters
with Diaryliodonium Triflates by Palladium Catalysis. J. Org.
Chem. 2019, DOI: 10.1021/acs.joc.9b00605.
69.
Whitaker, D.; Burés, J.; Larrosa, I., Ag(I)-Catalyzed C–
H Activation: The Role of the Ag(I) Salt in Pd/Ag-Mediated C–H
Arylation of Electron-Deficient Arenes. J. Am. Chem. Soc. 2016,
138, 8384-8387.
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Journal of the American Chemical Society
Page 10 of 11
70.
Wang, J.; Li, R.; Dong, Z.; Liu, P.; Dong, G.,
Synthesis of the Biaryl Core of Anacetrapib via a Ruthenium-
1
2
3
4
5
6
7
8
Complementary site-selectivity in arene functionalization enabled
by overcoming the ortho constraint in palladium/norbornene
catalysis. Nature Chem. 2018, 10, 866-872.
Catalyzed Direct Arylation Reaction: Unexpected Effect of Solvent
Impurity on the Arylation Reaction. J. Org. Chem. 2011, 76, 1436-
1439.
71.
N,N-Diallyl-3-iodobenzoate did not react, although both
79.
Vicente, J.; Saura-Llamas, I.; Palin, M. G.; Jones, P. G.;
halide and amine starting materials were recovered. 1-(Allyloxy)-
4-iodobenzene gave recovery of the amine starting material and 4-
iodophenol. 4-Iodostyrene gave recovery of amine starting material
and an intractable solid which was believed to be some polymer. 4-
Iodophenyl cholesterol carbonate decomposed during the reaction
to give cholesterol and 4-iodophenol, while reaction with
cholesterol 4-iodobenzoate gave recovery of amine and halide
starting materials.
Ramírez de Arellano, M. C., Orthometalation of Primary Amines.
4.1 Orthopalladation of Primary Benzylamines and (2-
Phenylethyl)amine. Organometallics 1997, 16, 826-833.
80.
Chen, K.; Wang, D.; Li, Z.-W.; Liu, Z.; Pan, F.; Zhang,
Y.-F.; Shi, Z.-J., Palladium catalyzed C(sp3)–H acetoxylation of
aliphatic primary amines to γ-amino alcohol derivatives. Org.
Chem. Front. 2017, 4, 2097-2101.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
81.
Fuchita, Y.;
Tsuchiya, H.; Miyafuji, A.,
72.
Shang, M.; Sun, S.-Z.; Dai, H.-X.; Yu, J.-Q., Cu(II)-
Cyclopalladation of secondary and primary benzylamines. Inorg.
Chim. Acta 1995, 233, 91-96.
Mediated C–H Amidation and Amination of Arenes: Exceptional
Compatibility with Heterocycles. J. Am. Chem. Soc. 2014, 136,
3354-3357.
82.
Clark, P. W.; Dyke, S. F., Palladium assisted organic
reactions: VII. The preparation of cyclopalladated primary and
secondary benzylamines. J. Organomet. Chem. 1985, 281, 389-
396.
73.
Zeng, W.; Nukeyeva, M.; Wang, Q.; Jiang, C., Synthesis
of unnatural α-amino acid derivatives via selective o-C–H
functionalization. Org. Biomol. Chem. 2018, 16, 598-608.
74.
W.; Kranemann, C. L.; Rische, T.; Eilbracht, P.; Kluwer, S.;
Ernsting, J. M.; Elsevier, C. J., Supercritical Carbon Dioxide as
Solvent and Temporary Protecting Group for Rhodium-Catalyzed
Hydroaminomethylation. Chem. Eur. J. 2001, 7, 4584-4589.
83.
Font, H.; Font-Bardia, M.; Gómez, K.; González, G.;
Wittmann, K.; Wisniewski, W.; Mynott, R.; Leitner,
Granell, J.; Macho, I.; Martínez, M., A kinetico-mechanistic study
on the C–H bond activation of primary benzylamines; cooperative
and solid-state cyclopalladation on dimeric complexes. Dalton
Trans. 2014, 43, 13525-13536.
84.
Haines, B. E.; Berry, J. F.; Yu, J.-Q.; Musaev, D. G.,
75.
Gair, J. J.; Haines, B. E.; Filatov, A. S.; Musaev, D. G.;
Factors Controlling Stability and Reactivity of Dimeric Pd(II)
Complexes in C–H Functionalization Catalysis. ACS Catal. 2016,
6, 829-839.
Lewis, J. C., Di-Palladium Complexes are Active Catalysts for
Mono-N-Protected Amino Acid Accelerated Enantioselective C-H
Functionalization. ChemRxiv 2019, 7665734.
85.
Vicente, J.; Saura-Llamas, I.; Grünwald, C.; Alcaraz,
76.
Smith, C. J.; Ali, A.; Hammond, M. L.; Li, H.; Lu, Z.;
C.; Jones, P. G.; Bautista, D., Palladium-Assisted Formation of
Carbon−Carbon Bonds. Part 10.1 Insertion Reactions of
Isocyanides into the Pd−C Bond of Orthopalladated Primary
Amines. Synthesis of 2-R-Aminoisoindolinium Salts (R = tBu, 2,6-
Xylyl). Organometallics 2002, 21, 3587-3595.
Napolitano, J.; Taylor, G. E.; Thompson, C. F.; Anderson, M. S.;
Chen, Y.; Eveland, S. S.; Guo, Q.; Hyland, S. A.; Milot, D. P.;
Sparrow, C. P.; Wright, S. D.; Cumiskey, A.-M.; Latham, M.;
Peterson, L. B.; Rosa, R.; Pivnichny, J. V.; Tong, X.; Xu, S. S.;
Sinclair, P. J., Biphenyl-Substituted Oxazolidinones as Cholesteryl
Ester Transfer Protein Inhibitors: Modifications of the
Oxazolidinone Ring Leading to the Discovery of Anacetrapib. J.
Med. Chem. 2011, 54, 4880-4895.
86.
Crovak, R. A.; Hoover, J. M., A Predictive Model for the
Decarboxylation of Silver Benzoate Complexes Relevant to
Decarboxylative Coupling Reactions. J. Am. Chem. Soc. 2018, 140,
2434-2437.
77.
Kapoor, M.; Chand-Thakuri, P.; Young, M. C., Carbon
Dioxide-Mediated C(sp2)–H Arylation of Primary and Secondary
Benzylamines. ChemRxiv 2018, 7138088.
78.
Marcoux, J.-F.; O’Shea, P. D.; Davies, I. W., Preparative Scale
Ouellet, S. G.; Roy, A.; Molinaro, C.; Angelaud, R.;
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