Palladium-Catalyzed Oxidation of β-C(sp3)-H Bonds of Primary Alkylamines through a Rare Four-Membered Palladacycle Intermediate

Article abstract of DOI:10.1021/jacs.0c01629

Site-selective functionalizations of C-H bonds are often achieved with a directing group that leads to five- or six-membered metallacyclic intermediates. Analogous reactions that occur through four-membered metallacycles are rare. We report a challenging palladium-catalyzed oxidation of primary C-H bonds β to nitrogen in an imine of an aliphatic amine, a process that occurs through a four-membered palladacyclc intermediate. The success of the reaction relies on the identification, by H/D exchange, of a simple directing group (salicylaldehyde) capable of inducing the formation of this small ring. To gain insight into the steps of the catalytic cycle of this unusual oxidation reaction, a series of mechanistic experiments and density functional theory (DFT) calculations were conducted. The experimental studies showed that cleavage of the C-H bond is rate-limiting and formation of the strained four-membered palladacycle is thermodynamically uphill. DFT calculations corroborated these conclusions and suggested that the presence of an intramolecular hydrogen bond between the oxygen of the directing group and hydroxyl group of the ligating acetic acid is crucial for stabilization of the palladacyclic intermediate.

Full text of DOI:10.1021/jacs.0c01629

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Article
Palladium-catalyzed oxidation of #-C(sp3)-H bond of primary
alkylamines through a rare four-membered palladacycle intermediate
Bo Su, Ala Bunescu, Yehao Qiu, Stephan J. Zuend, Martin Ernst, and John F. Hartwig
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.0c01629 • Publication Date (Web): 27 Mar 2020
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Palladium-catalyzed oxidation of β-C(sp3)-H bond of primary alkyla-
mines through a rare four-membered palladacycle intermediate
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Bo Sua, Ala Bunescua‡, Yehao Qiua‡, Stephan J. Zuendb, Martin Ernstc, and John F. Hartwiga*
aDepartment of Chemistry, University of California, Berkeley, Berkeley, California 94720, United States
bBASF Corp., 46820 Fremont Boulevard, Fremont, California 94538, United States
cBASF SE, Carl-Bosch-Straße 38, 67056 Ludwigshafen, Germany
‡Contributed equally
ABSTRACT: Site-selective functionalizations of C-H bonds are often achieved with a directing group that leads to five- or six-
membered metallacyclic intermediates. Analogous reactions that occur through four-membered metallacycles are rare. We report a
challenging palladium-catalyzed oxidation of primary C-H bonds β to nitrogen in an imine of an aliphatic amine, a process that occurs
through a four-membered palladacyclc intermediate. The success of the reaction relies on the identification, by a study on H/D ex-
change, of a simple directing group (salicylaldehyde) capable of inducing the formation of this small ring. To gain insight into the
mechanism of this unusual oxidation reaction, a series of mechanistic experiments and DFT calculations were conducted. The exper-
imental studies showed that cleavage of the C-H bond is rate-limiting, and formation of the strained four-membered palladacycle is
thermodynamically uphill. DFT calculations corroborated these conclusions and suggested that the presence of an intramolecular
hydrogen bond between the oxygen of the directing group and hydroxyl group of the ligating acetic acid that is crucial for stabilization
of the palladacyclic intermediate.
Introduction
Scheme 1. Transition metal-catalyzed C-H functionali-
zation of aliphatic amines
Aliphatic amines are important organic compounds that are
widely found in natural products, pharmaceuticals, and
agrochemicals.1 Therefore, the development of synthetic
methods that enable efficient synthesis or functionalization of
aliphatic amines has been
a
longstanding goal.2 The
functionalization of C(sp3)-H bond in alkylamines3 and their
derivatives4,3h,5 by transition-metal complexes has been pursued
because it can transform ubiquitous inert C(sp3)-H bonds of
these molecules to valuable functional groups that are usually
inaccessible or difficult to introduce by traditional methods.
Cyclometallation is a crucial step in the functionalization of C-
H bonds at specific sites by transition-metal catalysts.6 A wide
range of directing groups have been developed to promote
cyclometallation to form stable five- or six-membered
metallacyclic intermediates (Figure 1a, top left). Such
cyclometallation with alkylamines and their derivatives have
led to the functionalization at C-H bonds γ- or δ- to the nitrogen
atom.6c In contrast, reactions that occur by C-H bond activation
to form four-membered metallacycles are rare because
formation of a strained-ring intermediate is kinetically and
thermodynamically less favorable (Figure 1a, top right). Thus,
functionalization of an alkylamine derivative at the C-H bond β
to nitrogen is challenging,3a,3c-g,7,5l,8 and corresponding four-
membered metallacycles are only known in specific cases.3a,3c
For example, Gaunt and coworkers reported a seminal
palladium-catalyzed, β-C(sp3)-H activation of alkylamines
directed by the amine nitrogen to form strained aziridine
derivatives; however, the amines were limited to sterically
hindered, secondary amines (Figure 1a, bottom).3a
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To achieve the functionalization of β-C(sp3)-H bonds in
alkylamine derivatives, other more circuitous pathways have
been developed, but none of these involve four-membered
metallacyclic intermediates.5l,8-9 For example, Dong and
coworkers reported a palladium-catalyzed acetoxylation of β-
C(sp3)-H bond of alkylamines to form 1,2-amino alcohol
derivatives by converting the alkylamines to hydrazone
derivatives, but this method is limited to secondary
carbinamines, requires three steps to install the directing group
on the nitrogen of the amine, and requires two steps to remove
the directing group after the C-H acetoxylation (Figure 1b).5l
Our group recently developed an iridium-catalyzed
intramolecular silylation of the β-C(sp3)-H bonds of secondary
amines.8 In combination with oxidation of the C-Si bond, this
reaction creates an alternative approach to form 1,2-amino
alcohols, but preparation of the hydrosilane was required and
the functional group tolerance of the synthesis of this silane
with LiAlH4 would limit application of this process. Thus,
functionalizations that occur through four-membered
metallacycles and direct oxidations of the β-C(sp3)-H bonds of
alkylamine derivatives are needed.
Here, we report an imine-directed acetoxylation of the β-C(sp3)-
H bonds of tertiary carbinamines under mild, neutral reaction
conditions by the formation of a four-membered palladacyclic
intermediate (Scheme 1c). The appropriate imine (from
salicylaldehyde)5b,5g was revealed by initial studies on H/D
exchange, and this directing group is inexpensive, readily
installed, removed and recovered. Mechanistic studies show C-
H bond cleavage is rate-limiting, and formation of the strained
four-membered pallacacycle is thermodynamically uphill.
to the hydroxyl group of the imine to form 2a-16 in 82% yield
without evidence for reaction at the C(sp3)-H bond.
Table 1. Pd-catalyzed C-H acetoxylation of amine de-
rivatives
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We
considered two possible origins of the lack of reactivity of
amine derivatives 1a-1 to 1a-15 and lack of reactivity of 1a-16
at the alkyl C-H bond based on the typical mechanism for pal-
ladium-catalyzed directed C-H oxidation (Figure 1). First,
cleavage of the C(sp3)-H bond might not occur because the bar-
rier to formation of a four-membered palladacycle B is too high.
Second, C(sp3)-H cleavage could occur, but the transition state
energy for subsequent oxidation of the Pd(II) intermediate B to
the Pd(IV) intermediate C is too high or formation of the pal-
ladacycle C is too endothermic.
Results and Discussion
1. Preliminary studies on the undirected C-H oxidation
of tert-butyl amine. tert-Butyl amine, the simplest tertiary car-
binamine, was selected as the model substrate to investigate the
β-C(sp3)-H oxidation of primary alkylamines because of the
utility of the corresponding oxidation product, 2-amino-2-
methylpropanol (AMP).10 Preliminary investigations focused
on reported conditions for platinum- and palladium-catalyzed
C(sp3)-H oxidation of free amines,11, 12 but no product derived
from C-H bond functionalization was observed (eq. 1). The lack
of reactivity of tert-butyl amine in the presence of the platinum
catalyst in acid could be explained by the combination of steric
hindrance and electron-poor property of the C–H bond of the
protonated amine.11 The lack of reactivity in the presence of the
palladium catalyst under more neutral conditions can be at-
tributed to coordination of tert-butyl amine, leading to deacti-
vation of the catalyst.7
Figure 1. Proposed catalytic cycle for the b-C-H functionalization
2. Identification of a suitable directing group. Further
studies involving directing groups6c on nitrogen led to function-
alization of the b-C-H bond, but the reactions required substan-
tial investigation. A series of auxiliary groups were installed on
the nitrogen of tert-butyl amine to form the corresponding
amine derivatives 1a-1 to 1a-16 (Table 1). Under commonly
employed conditions for the acetoxylation of C(sp3)-H bonds
(10 mol% Pd(OAc)2, 1.2 equiv of PhI(OAc)2, in AcOH at 100-
To distinguish between these possibilities, a set of H/D-
exchange experiments was conducted in the absence of oxidant
(Scheme 2). The combination of tert-butyl amine derivatives
1a-1 to 1a-16, Pd(OAc)2 (10 mol%), and AcOD (2.0 equiv)
were heated in CHCl3 at 80 oC for 12 h. No detectable
incorporation of deuterium into 1a-1 to 1a-15 was observed by
2H NMR spectroscopy, showing that cleavage of the C–H bond
in these substrates does not occur. In contrast, H/D exchange
with 1a-16 occurred at the C(sp3)-H bonds; 9.3% of the
hydrogen atoms in the tert-butyl group of 1a-16 were
deuteriated, indicating that the C(sp3)-H bond activation
o
120 C),4b,4c,13 none of the reactions of 1a-1 to 1a-15 gave any
detectable product from acetoxylation; the reaction with 1a-16
gave the product from acetoxylation at the C(sp2)-H bond para
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occurred with the imine derived from salicaldehyde. These data
benzene gave a 4:1 mixture of acetoxylated products mono-2a
and di-2a in a combined 51% yield (entry 3). Reactions
conducted with a series of added bases showed that weak bases
had little effect on the yield (entries 3, 11-14). Reactions with
some of the ligands14 currently used for palladium-catalyzed
oxidation showed that the reaction with N-(tert-
butoxycarbonyl)-L-alanine (N-Boc-Ala) occurred in a slightly
higher 58% yield than that without ligand (51%) (entry 15, see
supporting information for more details). In this reaction 10-20%
of the reactant remained, leading to a mass balance of 70-80%;
no side product formed in greater than 5% yield.
indicate that cleavage of the C(sp3)-H bond in 1a-16 occurs
under more neutral conditions without activation of the aryl C-
H bond that underwent oxidation in neat acidic acid. Yu
recently investigated salicylaldehyde and its analogs
systematially as a transient directing group for the arylation of
the γ-C-H bonds in alkylamines.5g,5k However, the
functionalization of the b-C-H bond in alkylamines with
these type of directing groups or others (eg. picolinic acid,
8-quinolinecarbaldehyde, etc.) has not been observed.
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Scheme 2. H/D exchange experiments
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Table 3. Scope of the β-acetoxylation of amine deriva-
X
X
tives
N
N
% Da
AcOD (2.0 equiv)
Pd(OAc)2 (10 mol%)
Me Me
Me
1a-n
Me Me
Me
1a-n-D
CHCl3, 80 oC, 12 h
X
OH
N
0%
N
9.3% D
Me Me
Me
Me Me
Me
1a-16-D
1a-1-D to 1a-15-D
aPercent of all nine hydrogens in the t-butyl group that are deuteriated
Table 2. Evaluation of the conditions for the acetoxylation
of compound 1a
4. Scope of the β-C(sp3)-H bond acetoxylation. The scope of
the acetoxylation of amines under the developed conditions via
imine 1a is shown in Table 3. Reactions of imines from tertiary
carbinamines containing a range of substitution patterns and
functional groups on the amine afforded isolated products from
acetoxylation of the β-C(sp3)-H bonds in moderate yields. In
most cases, conversion of the starting substrate was greater than
80%; the mass balance consisted of multiple products from side
reactions. The acetoxylation of the β-C(sp3)-H bond of imines
1a–1c bearing a series of alkyl substituents afforded the
corresponding products (2a–2c). The ratio of mono-
acetoxylation product to di-acetoxylation product was higher
for the examples containing a smaller alkyl substituent. The
acetoxylation also occurred in the presence of a variety of
3
3. Development of the β-C(sp3)-H bond acetoxylation.
Having shown that the C(sp3)-H bond of the salicylaldimine
1a-16 (hereafter abbreviated as 1a) undergoes cleavage, we
considered that solvent and acidity could influence the
selectivity for functionalization of the sp2 versus sp3 C–H bonds
(compare results in Table 1 and Scheme 2) and enable oxidation
of the Pd-C bond of palladacycle B. Indeed, in the absence of
acetic acid in nonpolar solvents, the product from acetoxylation
of the C(sp3)-H bond was obtained (Table 2). Among the
reactions conducted in non-polar solvents, the reaction in
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functional groups (1d-1k), including benzyl and alkyl ethers
external ligands, such as triphenyl phosphine and pyridine, were
added to the reaction of 1a with Pd(OAc)2, but no palladacycle
formed from cleavage of the C(sp3)-H bond. Consistent with
these synthetic studies, no palladacyclic intermediate was ob-
served during the catalytic reactions (eq 4-6), as judged by anal-
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4
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(1d and 1e), a silyl ether (1f), an ester (1g), a carbamate (1h), a
carbonate (1i), an alkene (1j), and an amide (1k). The yield
from acetoxylation on a larger scale was similar to that on
smaller scale (Table 3, substrate 1a).
1
ysis of the crude reaction mixture by H NMR spectroscopy.
The regioselectivity and yield for the acetoxylation depended
on the architecture of the alkyl group. Acetoxylation of 1l,
which contains both γ- and β-methyl C-H bonds, occurred
predominantly at the γ-methyl C-H bonds through a more
favorable five-membered palladacycle intermediate. The site of
acetoxlylation of 1m and 1n, which contain both secondary γ-
C(sp3)-H bonds and unactivated primary β-C(sp3)-H bonds,
depended on the nature of the substituents on the secondary
carbon. Reaction of 1m containing a benzyloxy substituent at
the γ methylene position gave a 1:1 mixture of products from
reaction at the primary β-C(sp3)-H bond and secondary γ-
C(sp3)-H bond , while reaction with substrate 1n containing an
alkoxycarbonyl group at the γ methylene position gave the
product from acetoxylation at the acidic secondary γ-C(sp3)-H
bond exclusively.15 Imine 1o containing a single β methyl group
and imine 1p derived from a secondary, rather than tertiary,
carbinamine did not react.
This set of mechanistic suggest that the formation of the four-
membered palladacycle is unfavorable and could lie uphill from
the salicylaldimine complex 4.
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5. Installation, removal and recovery of the directing group.
Installation and removal of the directing group are efficient and
operationally simple, and the directing group is recoverable.
The imine 1a was obtained almost quantitatively (96%) by
condensation of tert-butyl amine with salicylaldehyde in DCM
at room temperature (eq 2). To demonstrate the ability to
remove and recover the directing group, mono-2a was
subjected to a 1.0 M aqueous solution of HCl at 80 oC (eq 3).
The salicylaldehyde was removed and recovered in 96% yield,
based on the amount of mono-2a. After basification of the
aqueous solution, followed by extraction by organic solvent
(DCM), the free amino alcohol was obtained in 80% yield.
To test if a salicylaldimine-ligated palladium is capable of
forming a metallacycle by cleavage of a C(sp3)-H bond, we al-
lowed Pd(OAc)2 to react with substrate 1l that could form a
five-membered palladacycle under the same conditions as the
reaction with 1a. Indeed, the five-membered palladium com-
plex 5’ formed in quantitative yield, as determined by 1H NMR
spectroscopy (eq 7). Although complex 5’ is stable in solution,
it decomposed during attempts to purify by various methods.
Thus, an external ligand (3,5-bis(trifluoromethyl)phenyl)phos-
phine was added to the crude reaction mixture of 5’ to form a
more stable complex 7, which was isolated by silica gel column
chromatography in 86% yield. The structures of palladium
complexes 4, 6, and 7 were confirmed by X-ray crystallography
(Figure 2).
6. Mechanistic investigation. To determine whether cleav-
age of the C-H bond or oxidation of the Pd-C bond is rate-lim-
iting and to gain insight into the thermodynamics for formation
of the four-membered palladacycle, we conducted synthetic or-
ganometallic studies of cyclopalladated species. Reaction of
o
imine 1a with 1.0 equiv of Pd(OAc)2 at 80 C formed a dinu-
clear bis-µ-acetatopalladium complex 4 in 39% yield. No cy-
clopalladated complex 5 formed (eq 4). The same reaction in
the presence of base (e.g. Na2CO3) to promote the C-H bond
cleavage formed the palladium complex 6 containing two
deprotonated salicaldimines, but, again, no cyclopalladated spe-
cies formed (eq 5). Stoichiometric reactions were also con-
ducted with 1a-17 that contains a bulky tert-butyl substituent at
the ortho position of the hydroxyl group on the aryl group, but
the cyclopalladated species was again absent (entry 6). To po-
tentially stabilize the four-membered palladium intermediate,
Figure 2. Solid-state structures of 4, 5, and 7 determined
by single crystal X-ray diffractions.
To probe whether the β-C(sp3)-H bond was cleaved revers-
ibly under the conditions of the acetoxylation, we ran the cata-
lytic reaction of 1a in the presence of 2.0 equiv of AcOD and
1.5 equiv of PhI(OAc)2 to partial conversion. After 1 h at 80 oC
(eq 8), 1H NMR analysis of the crude reaction mixture showed
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that 47% of the starting material 1a remained (16% of the ace-
by 13.8 kcal/mol. The computed diffference in energy between
the analogous structures 5’ and 10’ containing the hydrogen
bond is 14.2 kcal/mol. Thus, the formation of the four-
membered palladacycle 5 is computed to be thermodynamically
uphill of monomeric salicaldimine complex 9 by 1.3 kcal/mol
and uphill of the isolated dimeric analog 4 by 10.6 kcal/mol,
whereas formation of the five-membered pallacycle 5’ is
computed to be downhill of monomeric 9’ by -8.8 kcal/mol and
nearly thermoneutral with the dimeric complex 4’. These results
corroborate our experimental observation of the formation of
five-membered palladacycle 5’ from 4’ but our detection of the
formation of the four-membered ring palladacycle 5 only
indirectly by H/D exchange experiments in the absence of
oxidant (see Scheme 2).
1
2
3
4
5
6
7
8
toxylated product 2a formed), and no deuterium had been in-
2
corporated into the unreacted 1a, as determined by H NMR
spectroscopy. These data indicate that the C-H cleavage is irre-
versible and, therefore, that oxidation of the metallacyclic inter-
mediate is more rapid than reversion to the acyclic precursor.
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To gauge the rate of the oxidation of a palladacycle derived
from the salicylaldimines, we studied the oxidation of the five-
membered metallacycle 5’ generated in solution (eq 9). The re-
action of 5’ with 2 equiv of PhI(OAc)2 occurred to completion
at room temperature in less than 5 min to form the C acetox-
ylated complex in 46-50% yield. These data are consistent with
rapid oxidation of the four-membered palladacycle at 80 °C that
is required for irreversible formation of the metallacycle.
DFT calculations on the remainder of the reaction pathway are
included in Figure 3. Oxidation of both palladacycles 5 and 5’
by PhI(OAc)2 was computed to be thermodynamically downhill
by ~20 kcal/mol. The resulting Pd(IV) intermediates 11 and 11’
are computed to undergo nearly thermoneutral dissociation of
HOAc to form complexes 12 and 12’, which subsequently
undergo reductive elimination to form acetoxylated products 8
and 8’ in which the functionalized salicaldimine remains bound
to palladium.16 The free energy barriers for reductive
elimination from intermediates 12 and 12’ were calculated to be
12.2 and 15.4 kcal/mol, respectively. A comparison of these
barriers to the 22.5 and 17.9 kcal/mol barriers for C-H bond
cleavage imply that C–H activation is irreversible and turnover-
limiting for the catalytic acetoxylation process. This conclusion
is consistent with the lack of incorporation of deuterium into the
reactant under the conditions of the catalytic process.
H
O
O
O
PhI(OAc)2 (2.0 equiv)
CDCl3, rt, 5 min
O
O
(eq 9)
Pd
Pd
N
N
O
Me
Me
OAc
Me
5’
Me
8'
7. DFT calculations of the catalytic acetoxylation. To gain
insight into the thermodynamics for formation of a four-
membered metallacycle, we performed DFT calculations on the
catalytic acetoxylation process. These data are summarized in
Figure 3. We determined the barrier and thermodynamics for
cleavage of the β C-H bond of the bound salicaldimine by a
concerted metallation deprotonation process involving the
coordinated acetate in the monomeric complexes 9 and 9’
derived from the isolated dimeric complexes 4 and 4’. Quasi-
harmonic Gibbs free energies were calculated of the observed
dimeric salicaldimine palladium complexes 4 and 4’, the
monomeric 9 and 9’ that would undergo C-H bond cleavage,
the transition states for C–H activation by 9 and 9’ (TS(9-10)
and TS(9’-10’)) to form palladacycles 10 and 10’ containing a
bound acetic acid, and palladacycles 5 and 5’, which are
isomers of 10 and 10’, in which the carboxylic acid is engaged
in an intramolecular hydrogen bond. These calculations showed
that formation of the four-membered metallacycle is endergonic,
but formation of the five-membered metallacycle is exergonic.
Conclusion
In conclusoin, we developed
directed β-C(sp3)-H acetoxylation of tertiary carbinamines,
which likely proceeds through rare four-membered
a palladium-catalyzed,
a
palladacycle intermediate. Identification of the appropriate
group on the nitrogen of the amine to enable C-H activation
resulted from studies on the H/D exchange. The directing group
is inexpensive, readily installed, removed, and recovered.
Mechanistic studies revealed that the C(sp3)-H bond is cleaved
irreversibly and is the rate-determining step of the reaction.
DFT calculations were consistent with experimental results in
which the four-membered palladacycle was not observed
during the reaction but five-membered palladacycles formed
readily. The DFT studies suggest that formation of the four-
membered palladacycle is thermodynamically uphill, but the
formation of the corresponding five-membered palladacycle is
downhill. The combination of directing group on nitrogen to
facilitate formation of a four-membered metallacycle and
oxidant that reacts rapidly with the unstable metallacycle
enables this functionalization of the C-H bond of an amine to
occur, and these principles should facilitate the discovery of
additional reactions through such strained intermediates.
The free energy barriers for C–H activation within complexes 9
and 9’ to form the four-membered and five-membered
palladacycles 10 and 10’ are 22.5 and 17.9 kcal/mol,
respectively. The computed thermodynamics for the formation
of the metallacycle depended strongly on the presence or
absence of an intramolecular hydrogen bond involving the
coordinated acetic acid. The computed energy of the four-
membered palladacycle 5 containing the hydrogen bond is
lower in energy than palladacycle 10 lacking the hydrogen bond
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Figure 3. Quasi-harmonic Gibbs free energy (T = 353.15 K) profile of Pd-catalyzed α-acetoxylation of primary amines. Calculations
were performed at the B3LYP-d3/LANL2DZ + 6-31G(d)/SMD(benzene)//M06-d3/SDD + 6-311+G(d,p)/SMD(benzene) level of
theory.
assistance with NMR experiments and Dr. Nicholas Settineri for X-
ray crystallography. Instruments in the CoC-NMR are supported in
ASSOCIATED CONTENT
part by NIH S10OD024998. AB thanks the Swiss National Science
Foundation for a postdoctoral fellowship. BS thanks Dr. Yumeng
Xi for helpful discussion.
Supporting Information.
“The supporting information is available free of charge via the In-
ternet at http://pubs.acs.org.”
Experimental procedures, characterization of new compounds, X-
ray data, and computational details (PDF)
X-ray crystallographic data for compounds 4 (CIF)
X-ray crystallographic data for compounds 6 (CIF)
X-ray crystallographic data for compounds 7 (CIF)
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AUTHOR INFORMATION
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Corresponding Author
* jhartwig@berkeley.edu
ORCID
Bo Su: 0000-0002-1184-0828
Ala Bunescu: 0000-0002-3880-8182
Yehao Qiu: 0000-0002-2650-0703
Stephan Zuend: 0000-0002-4420-000X
John F. Hartwig: 0000-0002-4157-468X.
ACKNOWLEDGMENT
This work was supported by BASFthrough the California Research
Alliance (CARA) and Computation Facility at UC Berkeley for
DFT calculations. We gratefully acknowledge Dr. Hasan Celik for
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