Carbon Dioxide-Driven Palladium-Catalyzed C-H Activation of Amines: A Unified Approach for the Arylation of Aliphatic and Aromatic Primary and Secondary Amines

Article abstract of DOI:10.1055/s-0037-1611381

Amines are an important class of compounds in organic chemistry and serve as an important motif in various industries, including pharmaceuticals, agrochemicals, and biotechnology. Several methods have been developed for the C-H functionalization of amines

Full text of DOI:10.1055/s-0037-1611381

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Carbon Dioxide-Driven Palladium-Catalyzed C–H Activation of
Amines: A Unified Approach for the Arylation of Aliphatic and
Aromatic Primary and Secondary Amines
Mohit Kapoor
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Pratibha Chand-Thakuri
Justin M. Maxwell
Daniel Liu
Hanyang Zhou
Michael C. Young*
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Department of Chemistry and Biochemistry, School of Green
Chemistry and Engineering, The University of Toledo, Toledo,
OH, 43606, USA
michael.young8@utoledo.edu
Received: 24.10.2018
Accepted after revision: 14.11.2018
Published online: 08.01.2019
DOI: 10.1055/s-0037-1611381; Art ID: st-2018-p0694-sp
Abstract Amines are an important class of compounds in organic
chemistry and serve as an important motif in various industries, includ-
ing pharmaceuticals, agrochemicals, and biotechnology. Several meth-
ods have been developed for the C–H functionalization of amines using
various directing groups, but functionalization of free amines remains a
challenge. Here, we discuss our recently developed carbon dioxide driv-
en highly site-selective γ-arylation of alkyl- and benzylic amines via a
palladium-catalyzed C–H bond-activation process. By using carbon di-
oxide as an inexpensive, sustainable, and transient directing group, a
wide variety of amines were arylated at either γ-sp3 or sp2 carbon–hy-
drogen bonds with high selectivity based on substrate and conditions.
This newly developed strategy provides straightforward access to im-
portant scaffolds in organic and medicinal chemistry without the need
for any expensive directing groups.
Mohit Kapoor (Far Right) obtained his Ph.D. from National Tsing Hua
University (Prof. Jih Ru Hwu) working on synthetic chemistry and me-
dicinal chemistry. His current research at The University of Toledo in-
volves developing more sustainable strategies for C–H activation.
Pratibha Chand-Thakuri (Far Left) obtained her B.S. and M.S. from
Tribhuvan University, Nepal. She is now pursuing her PhD at the Univer-
sity of Toledo, where she has been working in CO2-directed C–H activa-
tion aimed at developing reactions with new coupling partners.
Justin M. Maxwell (Second from Right) obtained his B.S. in Biology
from The University of Toledo, where he is now pursuing an M.S. in
Chemistry. His work is primarily in the area of developing new biologi-
cally active amines using CO2 as a directing group.
Daniel Liu (Left of Center) is a high school student participating in the
Ohio College Credit Plus program, and has been enrolled in various un-
dergraduate courses in Chemistry and Mathematics over the past three
years at The University of Toledo, where he has also been working in the
area of CO2-directed C–H activation.
1
2
3
4
5
Introduction
C(sp3)–H Arylation of Aliphatic Amines
C(sp2)–H Arylation of Benzylamines
Mechanistic Questions
Future Outlook
Key words C–H activation, carbon dioxide, amines, sustainable
chemistry, organometallics, synthetic methodology
1 Introduction
Hanyang Zhou (Second from Left) obtained his B.S. in Biology from In-
diana State University, and M.S. in Chemistry from Ball State University.
He is currently a PhD student at The University of Toledo, focusing on
C(sp3)-H arylation of amino acid-derived substrates mediated by CO2.
Michael C. Young (Right of Center) obtained his Ph.D. (Prof. Richard J.
Hooley) at the University of California – Riverside studying molecular
self-assembly. After a brief postdoctoral stint at the University of Texas
– Austin (Prof. Guangbin Dong) investigating new directing group ap-
proaches for C–H alkylation of ketones, he began his independent ca-
reer at The University of Toledo in 2016, where his group searches for
more sustainable approaches to organometallic synthetic methodology.
Amines are a pervasive functional group in a variety of
molecules, and they are especially important in the phar-
maceutical, agrochemical, and polymer industries.1 While
there are many classical approaches to synthesizing amines
from other functional groups,2 a growing trend is to ap-
proach the formation of complex molecules through Pd-
catalyzed C–H activation.3 In this way, more complex moi-
eties can be added to a pre-existing amine, allowing molec-
ular complexity to be doubled in a single synthetic step.4
There are numerous challenges with performing C–H acti-
© Georg Thieme Verlag Stuttgart · New York — Synlett 2019, 30, A–F

B
M. Kapoor et al.
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vation on amine substrates, however. First, amines are sen-
sitive to oxidation in the presence of transition metals.5
Second, free primary and secondary amines only serve as a
viable directing group (DG) for transition-metal-catalyzed
C–H activation in a few specific examples (many from the
Gaunt group), such as for sterically congested secondary
amines (Scheme 1a),6 as well as benzylic7 and homobenzyl-
ic8 amines.
licylaldehydes were also a viable directing group. Very re-
cently, the Bull group provided an alternative to using oxi-
datively sensitive aldehydes by instead introducing their
aldehyde directing group as the more stable acetal.29
Despite these advances, we reasoned that there was still
room for improvement: imines are sensitive to numerous
side reactions, and although useful for relatively mild aryla-
tion reactions, they are not likely to be viable intermediates
for reactions requiring more harsh or oxidizing conditions,
such as C–H oxidation or acetoxylation. Additionally, the
use of imines formed in situ as directing groups is only ap-
plicable to primary amines, leaving no viable strategy for
performing C–H activation of oxidizable secondary amine
substrates. Inspired by Larrosa’s use of aryl and heteroaryl
carboxylic acids as a traceless directing group for C–H acti-
vation,30 we set out to develop the use of carbon dioxide as
a transient directing group for the C–H activation of prima-
ry and secondary amine substrates (Scheme 1d). The hy-
pothesis was that the carbamate formed in situ would be
capable of binding to and thus direct the palladium catalyst
to promote site-selective C–H activation, while simultane-
ously deactivating the amine for side reactions, especially
oxidation.
b)
DG
DG
a)
H
M
N
NH
O
N
R
O
NH
R
PdLX
FG
γ
FG
γ
β
R
R
β
R
R
Strained Amine Directed Approach
Amide Functionality as Directing Group
Transient Directing Group Strategies
c) DG
d)
HO
NH2
M
NHR'
R'
R
O
N
R
N
γ
M
R
R
Ar
Ar
γ
R
R
R
R
Imine Functionality as Directing Group
Our Approach: CO2 Driven C-H Activation
Scheme 1 Schematic representation of C–H activation of amines us-
ing different approaches
While tertiary amines are well established for directing
Pd-catalyzed C–H activation,9 historically, the most preva-
lent method to achieve directed C–H activation of amine
substrates entailed conversion of the amine into an amide,
often with a chelating group to more tightly bind to the
transition metal (Scheme 1b).10 By using this approach,
many groups, including Daugulis,11 Yu,12 Sanford,13 Shi,14
Chen,15 and Zhao16 among others have devised many ele-
gant transformations involving the C–H activation of amine
substrates to install new functional groups. However, these
approaches are often undermined by the poor step and
atom economy associated with installing and subsequently
removing these functional groups,17 assuming that they can
be removed in the presence of more labile functional
groups.18
To alleviate this challenge, a recent approach has been to
use transient directing groups.17 Pioneered by Jun for the C–H
activation of aldehydes (also called olefin hydroacylation),19
transient directing groups have grown in popularity for
achieving C–H activation of numerous ketone,20 aldehyde,21
and even phenol22 substrates. Initially used by Sames for
anilines,23 the first application of this approach to aliphatic
amines did not come until 2016, when the groups of Dong24
and Ge25 simultaneously published two distinct transient
directing groups for the γ-C(sp3)–H arylation of aliphatic
amines (Scheme 1c). The benefit of Ge’s approach was that
the directing group could be used catalytically in the reac-
tion, thus decreasing the overall waste associated with an
added directing group. Other reports followed from Yu26
and Kamenecka27 using a pyridine DG attached to an alde-
hyde, while Murakami28 showed that sterically hindered sa-
2 C(sp3)–H Arylation of Aliphatic Amines
The key to realizing carbon dioxide as a transient direct-
ing group involved an important mechanical quandary in
addition to the standard mechanistic questions: how does
one achieve satisfactory carbon dioxide pressure to pro-
mote the desired reactivity, while simultaneously allowing
facile reaction screening? In principle reactions can be per-
formed under one atmosphere of carbon dioxide pressure
by using standard equipment and techniques (Schlenk lines
or balloons), but if the desired reaction requires higher
pressures, more expensive apparatus are required. Inspired
by strategies for carbonylation chemistry that generate CO
in situ through either liquid31 or solid32 precursors, we real-
ized that carbon dioxide can also be introduced into a reac-
tion as a solid – using dry ice.33 By using this technique, we
observed that simple reaction vials could be pressurized
with between 2 – 20 atmospheres of carbon dioxide, there-
by facilitating the desired C–H transformation in better
yield than could be obtained at ambient pressures.34 The
use of inexpensive vials further led to increased screening
efficiency, as the cost of a reaction vial with a PTFE (polytet-
rafluoroethylene) lined cap is approximately 1/3000th the
cost of a comparably sized pressure reactor.
With the technology in hand to quickly screen multiple
reactions under moderate pressures of carbon dioxide, it
was short work to find conditions for the desired C–H aryla-
tion reaction (Scheme 2).35 For the C–H activation of prima-
ry amines, we found optimized conditions using 10 mol% of
Pd(OAc)2 as a precatalyst, 1.5 equiv of AgTFA as an additive
© Georg Thieme Verlag Stuttgart · New York — Synlett 2019, 30, A–F

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M. Kapoor et al.
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(important to activate the aryl halide electrophile), 2 equiv
of aryl iodide, 4 equiv of water (to help facilitate carbamate
formation), and between 1 and 2 equiv of CO2 in the form of
dry ice using acetic acid as the solvent. In the absence of
CO2, only trace product was observed.
the chiral amine led to a moderate level of diastereoselec-
tivity in the arylation of one of two prochiral methyl
groups. Even more noteworthy is that a rare example of
transannular methylene C–H activation was possible using
a rigid norbornylamine substrate.36
I
I
NH2
NH2
Pd(OAc)2 (10 mol%)
AgTFA (1.5 equiv)
Pd(OAc)2 (10 mol%)
AgTFA (1.5 equiv)
NH2
R
R
NH2
Me
Me
R
+
+
R
R
Me
Me
R
R
H
H
CO2 (1–2 equiv), H2O (4 equiv)
AcOH (0.30 M), 110 °C, 12–14 h
CO2 (1–2 equiv), H2O (4 equiv)
AcOH (0.30 M), 110 °C, 12–14 h
R
29 examples
79–31% Yields
15 examples
67–48% Yields
Representative Examples
NH2
Representative Examples
NH2
NH2
NH2
H2N
H2N
H2N
nHex
Me
ortho = 65%
meta = 69%
para = 71%
Me
Me
Me
Me
Me
CO2Et
Me
CF3
57%
64%
59%
63%
74%
66%
70%
NH2
NH2
NH2
Me
Me
NO2
Cl
F
Me
Me
Me
Me
NH2
NH2
Me
Me
EtO2C
Ph
Et
I
61%
68%
Me
NH2
OH
CO2Et
NH2
NH2
O
NH2
X-Ray
of R = Ph
with AcOH
58%a
61%a
3.3:1 d.r.
R = H, 53%a
R = Ph, 62%a
Me
R
Me
Me
Me
Me
O
Me
OMe
meta = 79%
para = 78%
Ph
57%a
31%
Ph
Scheme 3 Amine substrate scope for γ-C(sp3)–H arylation directed by
CO2. a Temperature reduced from 110 to 90 °C.
Scheme 2 Aryl iodide substrate scope for γ-C(sp3)–H arylation of 1°
amines directed by CO2. a AgOTf used in place of AgTFA.
Gratifyingly, the transformation could also be per-
formed on secondary amines containing oxidizable C–N
bonds (Scheme 4). This represents a substrate class that is
inaccessible with all of the direct or transient directing
group approaches reported to date. To facilitate the reac-
tion, it was necessary to use a lower temperature, as well as
to dramatically increase the CO2 loading from a mere 1–2
equiv up to approximately 30 equiv. When the CO2 loading
was not increased, low conversion into C–H arylation prod-
ucts was observed, with concomitant oxidation and hydro-
lysis of the more sensitive C–N linkages. Both aliphatic and
benzylic/homobenzylic amines were viable for this trans-
formation, even when both side chains contained oxidiz-
able C–N bonds. This shows the utility of CO2 not only as a
directing group, but also as an in situ formed protecting
group, as has been previously demonstrated by Leitner.37 It
is worth considering that, in many of these examples, selec-
tivity is observed for C(sp3)–H bonds even in the presence
of what would normally be considered more reactive
C(sp2)–H bonds. Similar selectivity has recently been ob-
served by Gaunt,38 and the selectivity most likely derives
from a more favorable conformation for C–H activation on
the more sterically congested side of the amine.
Performing the reactions at 110 °C, conversion was usu-
ally complete after between 12 and 14 h. The substrate
scope was broad with regard to aryl iodides, and F-, F3C-,
EtO2C-, O2N-, Me-, MeO-, BnO-, and Ph- substituents on the
aryl iodide were all tolerated. Even some heterocycles, in-
cluding N-tosylindole and a diphenylisocoumarin, could be
incorporated in the reaction. Interestingly, while ortho-sub-
stituted aryl halides are generally unreactive in C–H aryla-
tion reactions, the use of a Ag salt with a weaker Lewis base
(OTf instead of TFA) facilitated a number of these substrates
in the reaction as well. While the exact reason for this is un-
known, we do observe a lower reaction pH afterwards
when AgOTf is used in place of AgTFA.
The reaction also worked with a variety of primary
amines, bearing either carbocyclic or acyclic α-tertiary car-
bons (Scheme 3). It is noteworthy that when using an ami-
nofluorene substrate, complete selectivity was observed for
C(sp3)–H arylation, despite the proximity of more reactive
C(sp2)–H bonds. By lowering the temperature by 20 °C, it
was also possible to extend the chemistry to substrates
with α-secondary carbons. Interestingly, lowering the tem-
perature for the α-tertiary substrates was not effective, and
led to decreased conversion, while performing the reactions
at the higher temperature on α-secondary substrates led to
increased decomposition. Under the milder reaction tem-
perature, it was possible to achieve selective monoarylation
using 3-aminopentane (similar selectivity could not be
achieved using 3-amino-3-methylpentane). Notably, when
this chemistry was applied to a chiral aminoester, no loss in
ee was observed in the product. Moreover, the presence of
3 C(sp2)–H Arylation of Benzylic Amines
Generally C(sp2)–H bonds are more reactive for C–H ac-
tivation than their aliphatic analogues. It was surprising to
us, therefore, that there were limited examples of the γ-C–
H activation of benzylamines in the literature. To date, there
© Georg Thieme Verlag Stuttgart · New York — Synlett 2019, 30, A–F

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M. Kapoor et al.
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R2
I
R1
R2
R1
Pd(OAc)2 (10 mol%)
AgTFA (3.0 equiv)
NH
R2
NH
NH
Pd(OAc)2 (10 mol%)
AgTFA (2.0 equiv)
NH
I
R
72 examples
88–34% Yields
R2
R3
+
R
H
R1
CO2 (30 equiv), H2O (4 equiv)
HFIP/AcOH (1:1), 90 °C, 24 h
R3
+
R3
CO2 (5 equiv)
H2O (4.0 equiv)
R1
R3
HFIP/AcOH (0.7:0.3)
100 °C, 12–15 h
R
R
NH
R = C6H5, 50%
R = 4-MeOC6H4, 54%
R = 3-MeOC6H4, 53%
R = 4-MeC6H4, 51%
R = 3-MeC6H4, 52%
R = 2-C10H7, 47%
Me
Me
Representative Examples
F
NH2
F
NH2
F
NH2
F
NH2
F
NH2
NH
Ph
Me
NH
R = C3H7, 44%
R = C4H9, 45%
R = C5H11, 43%
Me
Me
Me
Me
F
CF3
F2HCO
OMe
43%
meta = 75%
para = 81%
meta = 64%
para = 63%
meta = 69%
para = 61%
meta = 57%
para = 57%
71%
Cl
HN
Ph
Me
NH
Et
NH
Et
Et
NH2
Cl
NH2
NH2
Me
Br
NH2
MeO
Me
CO2Et
41%
NH2
CO2Et
Ph
Et
48%
40%
Scheme 4 2° Amine substrate scope for γ-C(sp3)–H arylation directed
by CO2
CO2Et
CO2Et
CO2Et
NO2
CO2Et
CO2Et
61%
Cl
82%
77%
84%
80%
F
O
O
O
N
N
N
H
H
H
are only two examples of successful C–H arylation on ben-
zylamines, one using the amine directly,7b and one using a
transient DG approach.27 Notably, both approaches re-
quired harsh conditions (130 °C reaction temperature), and
were incompatible with pre-existing stereocenters, as well
as oxidizable secondary amine substrates. We considered
that our strategy using CO2 could facilitate a milder reaction
that would obviate the challenges associated with the pre-
vious approaches.39
Cl
CO2Et
CO2Et
66%
CO2Et
86%
72%
Selective Monoarylation with Chelating Substrates
OEt
P
OH
O
NEt2
O
OMe
O
OEt
NH2
NH2
NH2
NH2
CO2Et
CO2Et
CO2Et
CO2Et
69%
65%
61%
52%
After re-optimization of the conditions for aliphatic
amines,35 we were delighted to find that we could achieve
the selective γ-C(sp2)–H arylation of benzylamines with a
variety of aryl iodides (Scheme 5), including uncommon ex-
amples such as those containing F3CO-, F2HCO-, and even 2-
iodostrychnine. Again, in the absence of CO2, less than 10%
yield of the ortho-arylated products was obtained. Further-
more, the reaction had a relatively broad substrate scope for
both primary and secondary benzylamines, and numerous
carbocyclic and heterocyclic-containing substrates were
able to participate in the reaction without concomitant oxi-
dation or other side decomposition-pathways impacting
the synthetic utility.
Notably, when the substrates possessed an α-chiral
amine, complete retention of configuration was observed in
the products, which can be a challenge for these phenylgly-
cine derivatives.29 Another interesting feature of this strate-
gy was observed in the presence of chelating functional
groups. While diarylation is typically challenging to shut
down during C–H activation,7b,29,40 by incorporating chelat-
ing groups such as alcohols, carbonyls, or even phospho-
nates β to the amine, complete selectivity for monoaryla-
tion was observed.
Scheme 5 Scope of the γ-C(sp2)–H arylation of primary and secondary
benzylamines
4 Mechanistic Questions
Despite our design element of using CO2 as a directing
group, we recognized that, under the reaction conditions,
carbamate formation might not be favored. Although nu-
merous Pd-carbamato complexes are known, they have
typically been formed under basic conditions.41 In our
hands, the carbamate complexes were challenging to iso-
late. Attempted synthesis in situ during NMR experiments
showed evidence of carbamate formation under acidic con-
ditions, confirming that the carbamates could be accessed.
Formation of these carbamate adducts in the presence of Pd
gave different spectra, suggesting that Pd-carbamato com-
plexes could be accessed even under acidic conditions.
Attempts to tease the intermediates out by mass spec-
trometry led to the observation of an interesting adduct in-
volving two carbon dioxides, potentially implicating a
unique nine-membered palladacycle (Scheme 6a) (a similar
nine-membered metallacycle was recently supported com-
putationally in another work).42 Notably, under the opti-
mized conditions, no α or β C–H activation of methyl
groups (from a five-membered or six-membered palladacy-
cle respectively) could be achieved, suggesting that if a tran-
© Georg Thieme Verlag Stuttgart · New York — Synlett 2019, 30, A–F

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M. Kapoor et al.
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sient carbamate is serving as a directing group, it is more
likely to proceed through the larger ring intermediate.
However, none of this confirmed the actual role of CO2 in
the reaction. An alternative role for CO2 would be not as a
directing group, but to disrupt catalytically inactive Pd-
amine adducts.43 In our hands, we found that dissolution of
preformed Pd-amine adducts led to disproportionation,
suggesting that CO2 was not necessary to break up unreac-
tive aggregates (Scheme 6b).
periments lend a great deal of credence that our initial de-
sign of carbamates as an in situ directing group as the cause
for the observed reactivity.
5 Future Outlook
The use of CO2 has the potential to revolutionize the di-
recting groups that are used for C–H activation, as well as
other transformations that require directing groups. This
approach has the potential to be a viable directing group for
installation of numerous new functional groups at other-
wise inert C–H bonds. Additionally, while amines can react
with CO2, so too can other Lewis basic functional groups,
including alcohols, thiols, and phosphines. This lays the
foundation for carbon dioxide to serve as a unified directing
group approach for C–H activation of multiple functional
groups.
a)
O
O
NH2
Pd(OAc)2 (10 mol%)
O
Exact Mass Observed: 279.11
Exact Mass Calculated: 278.97
Matching Isotope Pattern
HN
O
H
CO2 (5 equiv)
H2O (4.0 equiv)
CDCl3/AcOH (0.7:0.3)
100 °C, 5 h
Pd
b)
OAc
Pd
NH2
H
N
H
N
Pd(OAc)2 (0.5 equiv)
Me
Acetic Acid-d4
Me
CDCl3, 60 °C, 12 h
82%
OAc
AcO
Pd
O
NH3 OAc
O
OAc
Pd
O
H
H
N
+
+
H
N
O
Pd
O
N
N
H
O
Me
Me
O
OAc
Me
Me
Funding Information
O
OAc
We are grateful to start-up funds from The University of Toledo as
well as the ACS Herman Frasch Foundation for Chemical Research
(830-HF17) in support of this work.()
c)
H2N
Pd(OAc)2 (10 mol%)
AgTFA (1.5 equiv)
I
NHCHO2
H2O (4.0 equiv)
AcOH, 110 °C, 12 h
+
64%
Acknowledgment
NH3
NH2
We wish to acknowledge Mr. Bishwa Bhetuwal for taking the group
photo for this manuscript.
MeO
MeO
Pd(OAc)2 (10 mol%)
AgTFA (2.0 equiv)
I
MeO
NHCHO2
+
H2O (4.0 equiv)
HFIP/AcOH (0.7/0.3)
100 °C, 13 h
NH3
CO2Et
CO2Et
References
57%
H
d)
H2N
H
Ar
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I
KIE = 3.2
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D2
C
D2
C
D
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D
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AcOH (0.3 M), 110 °C
H2N
H2N
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CO2Et
D
D
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Scheme 6 Mechanistic experiments for the CO2-mediated C–H activa-
tion of aliphatic and benzylamine substrates
To better assess the role of CO2, we prepared the ammo-
nium carbamate of both aliphatic amines and benzyl-
amines, and found that better than substoichiometric aryla-
tion with regard to the CO2 loading could be achieved
(Scheme 6c), suggesting that it could be used substoichio-
metric in the reaction. Further studies demonstrated strong
positive kinetic isotope effects for the aliphatic amine reac-
tion (Scheme 6d), while a more moderate KIE of 1.5 was ob-
served for the benzylamine reaction. It is noteworthy that
running the reactions under deuterated solvent conditions
led to no deuterium enrichment. Taken together, these ex-
© Georg Thieme Verlag Stuttgart · New York — Synlett 2019, 30, A–F

F
M. Kapoor et al.
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