Carbon Dioxide-Mediated C(sp3)-H Arylation of Amine Substrates

Article abstract of DOI:10.1021/jacs.8b05061

Elaborating amines via C-H functionalization has been an important area of research over the past decade but has generally relied on an added directing group or sterically hindered amine approach. Since free-amine-directed C(sp³)-H activation is still primarily limited to cyclization reactions and to improve the sustainability and reaction scope of amine-based C-H activation, we present a strategy using CO₂ in the form of dry ice that facilitates intermolecular C-H arylation. This methodology has been used to enable an operationally simple procedure whereby 1° and 2° aliphatic amines can be arylated selectively at their γ-C-H positions. In addition to potentially serving as a directing group, CO₂ has also been demonstrated to curtail the oxidation of sensitive amine substrates.

Full text of DOI:10.1021/jacs.8b05061

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Communication
Carbon Dioxide Mediated C(sp3)–H Arylation of Amine Substrates
Mohit Kapoor, Daniel Liu, and Michael C. Young
J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 22 May 2018
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Mohit Kapoor, Daniel Liu, Michael C. Young*
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Department of Chemistry and Biochemistry, School of Green Chemistry and Engineering, University of Toledo, Toledo,
OH, 43606.
Supporting Information Placeholder
while a recent report even suggests 1º amine or ammonium-di-
rected C(sp3)-H oxidation.12 1º and 2º amines, however, generally
require the presence of a directing group (DG) to facilitate C–C
bond forming C(sp3)-H activation.13 The only exception to this is
when 2º amine substrates are used bearing fully substituted α,α’-
centers.14 The strategy can also be applied to primary β-aminoalco-
hols by first converting them into highly substituted aminoketals,
although neither strategy enjoys a particularly broad substrate
scope.15
ABSTRACT: Elaborating amines via C–H functionalization has
been an important area of research over the last decade, but has
generally relied on an added directing group or sterically hindered
amine approach. Since free amine-directed C(sp3)–H activation is
still primarily limited to cyclization reactions, and to improve the
sustainability and reaction scope of amine-based C–H activation,
we present a strategy using CO2 in the form of dry ice that facili-
tates intermolecular C‒H arylation. This methodology has been
used to enable an operationally simple procedure whereby 1º and
The two traditional methods to facilitate DG-mediated C(sp3)–H
arylation of amines have been to use static functional groups, such
as amides with or without a second chelating moiety (Scheme 1b),16
while a recent trend has focused on transient DGs (Scheme 1c).17
Though each can be used to facilitate C(sp3)–H activation reac-
tions, both possess disadvantages that might be alleviated. Static
DGs require additional stoichiometric reagents, and are both atom
and step uneconomical. Meanwhile, transient DGs, generally based
on aldehyde-based DGs, suffer from the presence of oxidation-sen-
sitive imines as intermediates. Furthermore, static DGs are rarely
used for C–H activation of 2º amine substrates, while transient DG
methods are non-existent.
2º aliphatic amines can be arylated selectively at their γ-C–H posi-
tions. In addition to potentially serving as a directing group, CO2
has also been demonstrated to curtail the oxidation of sensitive
amine substrates.
Amines are a key functional group in pharmaceuticals,1 agro-
chemicals (Figure 1),2 as well as materials,3 and have been the sub-
ject of numerous synthetic approaches.4 Although transition metal-
catalyzed C–H activation has revolutionized the installation of
functional groups at otherwise inert C–H bonds,5 amines are still a
complicated substrate class for this strategy because of their reac-
tivity. Primary (1º) and secondary (2º) amines are especially sensi-
tive to oxidation, making them a challenge for organometallic re-
actions:6 palladium, for example, is well-known in its ability to ox-
idize 1º and 2º amines.7 Furthermore, amines can react with organ-
ometallics to produce substituted amines, such as in the Buchwald-
Hartwig coupling.8 Despite these challenges, there are examples of
palladium-catalyzed C–H activation of both 1º and 2º free-amine
substrates in the literature, yet these have generally featured either
activation of more reactive C(sp2)–H bonds,9 or intramolecular cy-
clization.10 We present herein an alternative strategy for overcom-
ing these barriers using carbon dioxide to mediate C‒H activation.
Scheme 1. Strategies for Amine-Directed C(sp3)–H Arylation.
To circumvent the challenges of these two strategies, we sought
a hybrid DG strategy (Scheme 1d). Carbon dioxide (CO2) was sub-
sequently identified as a viable candidate: it contains a carbonyl
that can reversibly react with amines, while the carbamate products
can readily coordinate to palladium but are more chemically robust
than imines.18 CO2 has previously been used as a traceless DG for
the meta-C–H activation of phenols (although requiring separate
and harsh installation and removal steps).19 We reasoned that CO2
could therefore serve as a transient DG in the presence of a suitable
nucleophile, such as an amine – both serving as a protecting group,
preventing substrate oxidation, as well as directing site selective C–
H bond scission by Pd. The use of a transient carbamate moiety as
a DG would have the potential to make C–H activation of 1º amines
feasible under more oxidizing conditions where simple ammonium
formation is inadequate to prevent amine oxidation, while simulta-
neously allowing expansion of a transient DG approach to 2º
amines.
Figure 1. Biologically-Active Compounds Bearing a γ-Arylamine
Motif.
Recent work has suggested that in situ protection of the amine as
an ammonium can be used to protect it from oxidation, thereby fa-
cilitating remote C(sp3)–H oxidation reactions by deactivation,11
We began our studies using the model substrate tert-amyl amine.
Previous work17 had shown that in the absence of a DG, only trace
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C–H arylation of this substrate is observed. Gratifyingly, using con-
ditions similar to Ge’s,17a we were able to selectively γ-arylate tert-
amyl amine using phenyl iodide in acetic acid with silver trifluoro-
acetate as an additive simply by performing the reaction under CO2
pressure (Table 1, 1a). As expected, the absence of any of these
components leads to only trace or no product. While the reaction
can occur under 1 atm of CO2 (see SI), we determined that the re-
actions could be easily screened in standard reaction vials by add-
ing CO2 in the form of dry ice. Approximately one-to-two equiva-
lents of dry ice could be added at 0.3 mmol scale, and the vials
immediately sealed to achieve satisfactory pressure to promote the
desired C‒H activation without concomitant failure of the vials (see
SI for further details and notes on safety). Interestingly, no exoge-
nous ligand was required to facilitate this transformation.
donating substituents (1r – 1w), as well as iodides with extended
conjugation (1x and 1y) are also tolerated in the reaction. While use
of ortho-functional groups other than a chelating ester were not tol-
erated using the standard conditions, switching the silver additive
to AgOTf allowed substituents with ortho-fluoro (1z) and hydroxyl
(1aa) groups to participate in the reaction. The reason for this mod-
ulation of reactivity is not clear at the present time, although the
reaction using AgOTf is more acidic than the AgTFA reaction by
~1 pH unit.
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Table 2. 1º Amine Substrate Scope for γ-C(sp3)–H Arylation Di-
rected by CO2. a 90ºC. b From isolated Bz products. c Extra AcOH
molecule removed for clarity.
Considering the amine scope, substrates containing saturated (2a
– 2d) and unsaturated (2e) carbocycles all participate in the reaction
with relatively good yields. The precursor for 2d was an insepara-
ble mixture of cis (major) and trans (minor) isomers, yet we were
able to cleanly isolated the cis isomer of 2d after the reaction (the
minor trans isomer also gave product, although this could not be
cleanly isolated). While 2e has more reactive γ-C(sp2)–H bonds,
good selectivity was observed for arylation of only the C(sp3)–H
bond. This selectivity can be rationalized due to the inflexibility of
the fused rings, which likely prevents the more reactive C–H bonds
from accessing the coordinated palladium catalyst. As long as a sin-
gle type of γ-C–H bond is present on the substrate, good selectivity
could be achieved despite the length of other aliphatic chains (2f
and 2g). When there were symmetrical positions with γ-C–H
bonds, however, a mixture of mono and diarylation was observed
(2h and 2i), albeit with some selectivity for mono and diarylation
only – triarylation was not observed when three separate ethyl
groups were attached (2i).
Table 1. Aryl Iodide Substrate Scope for γ-C(sp3)–H Arylation of
1º Amines Directed by CO2. a AgOTf used in place of AgTFA.
With the optimized conditions in hand, we first explored the
range of aryl iodides that could participate in the reaction. In gen-
eral, electron poor aryl iodides containing fluorides, trifluorome-
thyls, and esters were all effective in the reaction (Table 1, 1b – 1l).
While ortho-substituents are often challenging in C–H activation
reactions, the presence of an ortho-ester is well tolerated, likely due
to a chelate effect that promotes rather than inhibits oxidative addi-
tion to the C–I bond.20 Halophenyl iodides are also tolerated (1m –
1o), with no sign of activation of either aryl chlorides or bromides.
Even a diiodide gives good selectivity for monofunctionalization
(1o), while both halides can be functionalized in the presence of
excess amine (see SI). More complex heterocycles can also partic-
ipate in the reaction (1p and 1q), although with somewhat limited
success due we suspect to partial decomposition of the heterocycles
during the reaction. Iodides with moderate and strongly electron
We found that the 1º amine substrates did not require an α-ter-
tiary center, and less substituted substrates could also participate in
the reaction simply by lowering the temperature (2j – 2m). Despite
symmetrical γ-C–H bonds in both 2k and 2m, only monoarylation
was observed. The enhanced selectivity for monoarylation (com-
pared to 2h and 2i) is likely due to the decreased reaction tempera-
ture. Despite the presence of a chelating ester moiety, the ethyl ester
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of valine could be selectively arylated once to give the unnatural
amino acid product (2n). This compound was functionalized with
retention of the (S)-stereocenter of valine, and with moderate dia-
stereoselectivity (see SI). We were delighted to find that using a
rigid bornylamine in which there is a 1º γ-C–H bond that cannot be
reached by the catalyst, selective transannular arylation at a meth-
ylene γ-C–H bond position was achieved instead of at the methyl
group (2n).21 Using a larger biphenyl iodide, a similar product
could be obtained (2m), which facilitated x-ray analysis to confirm
location of the aryl group.
AcOD, no deuteration was observed, suggesting that the concerted
metalation-deprotonation step may be irreversible (Figure 2B).22
This was further corroborated by KIE experiments, which showed
a significantly faster reaction for the proteo-substrate.
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We next turned our attention to the challenge of whether or not
CO2 could also serve to promote the γ-C(sp3)–H arylation of 2º
amines, a transformation that had required highly substituted sub-
strates up to this point, generally gave β rather than γ-functionali-
zation, and which was inaccessible via imine-type DGs. Gratify-
ingly, the reaction could be performed by modifying our condi-
tions, most notably by increasing the CO2 loading. The excess CO2
was critical – at lower concentrations not only was the product yield
decreased, but significant oxidation of the starting material was ob-
served, giving a mixture of imine, amine, and aldehyde.
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Figure 2. Mechanistic Investigations of the CO2-Mediated γ-
C(sp3)–H Activation of Aliphatic Amine.
Although Pd–carbamato complexes are known,23 it is possible
that CO2 could actually have an off-cycle roll in this reaction. To
investigate whether or not CO2 was actually serving to disperse cat-
alytically inactive Pd-diamine complexes, we prepared complex 5
(Figure 2C).24 Dissolution of 5 in AcOH-d4 without CO2 was satis-
factory to partially dissociate the complex to give a mixture of the
trinuclear complex 6 and free ammonium, suggesting CO2 isn’t
necessary under the reaction conditions to disrupt formation of
complex 5. Meanwhile, introduction of CO2 into CDCl3 solutions
of this complex gave no change –extra base is required to facilitate
proton transfer to lead to stable Pd–carbamate complexes.23 To
simulate the reaction conditions, PdCl2 and amine were mixed in
1% AcOH in DMSO-d6, followed by bubbling CO2 through the so-
lution for 12 h. This gave a complex spectrum containing a carba-
mate signal, as well as new resonances between 121-124 ppm in
the 13C NMR from different CO2 species. We believe this supports
an on-cycle role for CO2 as a transient DG acting through a rare 7-
membered palladacycle,25 though further studies are needed.
Table 3. 2º Amine Substrate Scope for γ-C(sp3)–H Arylation Di-
rected by CO2.
The reaction tolerates 2º amines with different length alkyl sub-
stituents on the nitrogen (Table 3, 3a – 3c). Although 3a possesses
two distinct terminal γ-C–H bonds, the reaction occurs selectively
on the more substituted side, presumably due to more favorable
comformation during the C–H activation step.10a A homobenzylic
2º amine substrate was also tolerated without concomitant oxida-
tion (3d), as were a variety of benzylic amines, all with complete
selectivity observed for the γ-C(sp3)–H bond rather than function-
alization on the arene (3e – 3k). These are interesting substrates
both from the perspective of potentially competitive C(sp2)‒H
bonds, as well as to the sensitivity to oxidation. Again, the putative
more favored conformation during the reaction facilitates complete
selectivity for the less reactive C–H bonds, even though the in-
creased flexibility was initially predicted to lead to γ-C(sp2)–H
functionalization (2f). It is noteworthy that negligible oxidation of
the benzylic amines to the corresponding imines was observed in
these reactions, with significant mass balance being the unreacted
amine. Regrettably, increasing catalyst loading or adding the cata-
lyst portionwise failed to drive these reactions to completion, a re-
sult which demands further scrutiny to understand. Less substituted
2º amine substrates bearing a more oxidatively-sensitive α-2º cen-
ter could also be utilized (3l and 3m).
In conclusion, we have described the first example of a CO2 me-
diated amine C–H activation. The ability of CO2 to transiently form
carbamates may be useful not only for C–H activation, but also
other directing group mediated reactions. Furthermore, we antici-
pate that use of CO2, rather than a traditional protecting group, may
be a viable strategy for improving the sustainability of organic syn-
thesis. Work is underway in our lab to better understand the mech-
anism and intermediates at play in these reactions, as well as to fur-
ther develop the scope of these transformations.
Finally, we wanted to explore the mechanism and role of CO2 in
the reaction. Salt 4 was prepared and then subjected to the reaction
conditions without additional CO2, and gave greater than stoichio-
metric conversion with respect to CO2, suggesting that CO2 is act-
ing transiently (Figure 2A). When the reaction was performed in
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