Palladium-Mediated CO2 Extrusion Followed by Insertion of Isocyanates for the Synthesis of Benzamides: Translating Fundamental Mechanistic Studies to Develop a Catalytic Protocol

Article abstract of DOI:10.1021/acs.organomet.9b00820

Mechanistic studies of a stoichiometric palladium-mediated ExIn (ExIn = extrusion-insertion) decarboxylative amidation of aromatic carboxylic acids are presented, providing gas-phase and condensed-phase spectroscopic data, as well as theoretical computational evidence for intermediates in a proposed stepwise process. The understanding gained from these mechanistic studies directed the development of a palladium-catalyzed procedure in which benzamides are obtained in good to high yields in a one-pot 30 min microwave irradiation assisted protocol. A combination of experimental data and DFT calculations reveals that certain ligand additives favor the selective formation of benzamides rather than the undesired protodecarboxylation side product.

Full text of DOI:10.1021/acs.organomet.9b00820

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Article
Palladium-Mediated CO2 Extrusion Followed by Insertion of
Isocyanates for the Synthesis of Benzamides: Translating
Fundamental Mechanistic Studies To Develop a Catalytic Protocol
Yang Yang, Allan J. Canty, Alasdair I. McKay, Paul S. Donnelly, and Richard A. J. O’Hair*
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ABSTRACT: Mechanistic studies of a stoichiometric palladium-
mediated ExIn (ExIn = extrusion−insertion) decarboxylative
amidation of aromatic carboxylic acids are presented, providing gas-
phase and condensed-phase spectroscopic data, as well as theoretical
computational evidence for intermediates in a proposed stepwise
process. The understanding gained from these mechanistic studies
directed the development of a palladium-catalyzed procedure in which
benzamides are obtained in good to high yields in a one-pot 30 min
microwave irradiation assisted protocol. A combination of exper-
imental data and DFT calculations reveals that certain ligand additives
favor the selective formation of benzamides rather than the undesired
protodecarboxylation side product.
NR).10 The decarboxylation and insertion steps are directly
related, as CO2, RNCS, and RNCNR are all isoelectronic.
INTRODUCTION
■
The amide functional group is arguably the most important
structural motif in biology and chemistry. Nature uses amide
bonds within natural products, peptides, and proteins. Amide
bonds are also found in one out of four of all pharmaceuticals
on the market, as well as synthetic agrochemicals and
functional materials.1 The preparation of amides by the
condensation of carboxylic acids and primary amines is one
of the most widely used chemical reactions in contemporary
synthetic chemistry.2 However, forcing conditions are typically
employed, which limits the applicability to very robust
substrates. Stoichiometric coupling reagents, such as HATU
(1-[bis(dimethylamino)-methylene]-1H-1,2,3-triazolo[4,5-b]-
pyridinium-3-oxide hexafluorophosphate, Scheme 1A), have
been developed to overcome these limitations.3 While they are
widely used, such protocols produce stoichiometric amounts of
waste, which complicates the isolation of the desired amide
product.4,5 New methods for amide formation that overcome
this poor atom economy by activating alternative bonds are
highly desirable and form the basis of several new strategies
that include C−B and C−H bond activation.6−8
ArCO2H + RNCY → ArC(Y)NHR + CO2 Y = S, NR
(1)
In this report, we extend the scope of the ExIn class of
reactions to target the synthesis of benzamides (Scheme 1B, Y
= O) with the aim of developing an atom-efficient catalytic
procedure (Scheme 2). We restricted our study to 2,6-
dimethoxy- and 2,4,6-trimethoxybenzoic acids, as monosub-
stituted benzoic acids can undergo undesirable side reactions
involving Pd-mediated C−H bond activation at the positions
ortho to the carboxylate group.12,13 Although not a key
motivation for our work, it is worth noting that the
trimethoxybenzamide functional group has been demonstrated
recently to produce molecules that are selective inhibitors of P-
glycoprotein.14 Available thermochemical data suggest that the
formation of an amide via an ExIn reaction (eq 1, Y = O) is
exothermic by over 20 kcal/mol,15 with release of gaseous CO2
providing a further driving force. The key steps are likely to
involve binding of the carboxylate to the metal ion (eq 2,
Scheme 2), decarboxylation (eq 3, Scheme 2),16,17 insertion of
the isocyanate, RNCO, into the Pd−C bond (eq 4, Scheme 2)
affording the amidate complex 4,18−20 and release of the amide
5 from the metal ion (eq 5, Scheme 2). While many of these
We previously coined the term “ExIn” (extrusion−insertion)
to describe a new class of reactions for thioamide and amidine
synthesis (eq 1, Y = S, NR). In these isohypsic protocols
palladium(II) complexes mediate the decarboxylation of an
aromatic carboxylic acid, affording an organopalladium(II)
intermediate which subsequently inserts either an isothiocya-
nate or a carbodiimide followed by demetalation to afford the
thioamide (Scheme 1B, Y = S)9 or amidine (Scheme 1B, Y =
Received: December 2, 2019
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Scheme 1. Methods for Amide Synthesis: (A) C−OH Bond Activation Followed by C−N Bond Formation; (B) ExIn Approach
a
Involving C−C Bond Activation To Form an Organometallic Intermediate Followed by Insertion
a
X = OH, Y = S, see ref 9; X = OH, Y = NR, see ref 10; X = NHR, Y = O, see ref 11; X = OH, Y = O, this work.
Scheme 2. Reaction Scope of Catalytic Reactions (Left Column) and Mechanistic Study for the Synthesis of Amides Modeled
on the ExIn Protocol (Right Column)
individual steps have precedents, they have not been used
together to achieve a catalytic synthesis of benzamides directly
from benzoic acids (eq 1, Y = O).
benzoate to palladium-ligated amidate in the gas phase (eqs
6 and 7).
[(L)Pd(O2CAr)]+ → [(L)Pd(Ar)]+ + CO2
(6)
[(phen)Pd(Ar)]+ + RNCO → [(phen)Pd(NRC(O)Ar)]+
RESULTS AND DISCUSSION
(7)
■
Gas-Phase Studies of the Decarboxylation and
Isocyanate Insertion Steps. Multistage mass spectrometry
(MSn) experiments in a linear ion trap mass spectrometer and
DFT calculations were used to examine the key steps
associated with the transformation of palladium-ligated
We have previously shown that the organometallic cation
[(phen)Pd(Ar)]+ (9a, Figure 1a, phen = 1,10-phenanthroline)
can be generated by collision-induced dissociation (CID) of
CO2 from [(phen)Pd(O2CAr)]+ (6a).9 Decarboxylation is also
readily observed when the phen ligand is replaced by the more
B
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The identity of the ligand was found to have a negligible effect
on the energetics (Table 1). In contrast, replacing benzoic acid
with 2,6-dimethoxybenzoic acid resulted in intermediates and
TS7-8 lying at significantly lower energies and the overall
reaction became less endergonic (Scheme 3, Figure S3, and
Table 1). There are many literature reports of ortho-
substituted benzoic acid derivatives undergoing more facile
decarboxylation relative to their unsubstituted counterparts.23
The rollover cyclometalation pathway from 6c was also
calculated (Figure S2), and it is considerably less kinetically
and thermodynamically accessible, consistent with it being a
minor experimental product.
The gas-phase ion−molecule reactions (IMR) between the
coordinatively unsaturated organometallic ions 9 and phenyl
isocyanate were investigated (eq 7). Inspection of key spectra
(Figure 1b and Figure S4), and kinetic data (Table 2) reveals
Figure 1. LTQ MSn spectra of unimolecular and bimolecular
reactions associated with key steps of the ExIn reaction: (a) MS2
experiment involving extrusion of CO2 from [(phen)Pd(O2CC6H5)]+
(m/z 407) under CID at a normalized collision energy of 20 (eq 6);
(b) MS3 experiment involving an ion−molecule reaction between the
organometallic ion [(phen)Pd(C6H5)]+ (m/z 363) and phenyl
isocyanate (reaction time 300 ms) (eq 7); (c) MS4 experiment
involving CID on selected IMR product (m/z 482) at a normalized
collision energy of 20 (eq 7). The concentration of PhNCO in the
ion−molecule reaction is 1.1 × 1010 molecules cm−3. The mass-
selected ions are denoted by asterisks.
Table 2. Absolute Rates and Reaction Efficiencies of Ion−
Molecule Reactions between [(L)Pd(Ar)]+ and Phenyl
Isocyanate (Eq 7)
absolute rate/10−10 cm3
molecules−1 s−1
reaction
efficiency/%
reactant ion
(a) [(phen)Pd(C6H5)]+
0.88
8
(b) [(phen)Pd((CH3O)2C6H3)]+
(c) [(bpy)Pd(C6H5)]+
(d) [(bpy)Pd((CH3O)2C6H3)]+
(e) [(6mbpy)Pd(C6H5)]+
(f)[(6mbpy)Pd((CH3O)2C6H3)]+
no reaction
9.6
no reaction
2.4
79
20
flexible 2,2-bipyridine (bpy) or 6-methyl-2,2-bipyridine
(6mbpy) to afford the organometallic cations 9c,e, respectively
(Figure S1). In these instances, “rollover” cyclometalated
complexes were also formed as minor products (Figure
S1).21,22
The effect of the identity of the ligand and benzoic acid on
decarboxylation were investigated using density functional
theory (DFT) computation. These studies show that all
combinations of ligand and benzoic acid proceed via the same
pathway (Scheme 3 and Figure S2) in an endergonic manner.
no reaction
that [(phen)Pd(C6H5)]+ (9a) reacts at a rate of 8.8 × 10−11
cm3 molecules−1 s−1, corresponding to a reaction efficiency of
8% to afford an ion at m/z 482 as the major product ion
(Figure 1b and eq 7, Ar = C6H5). This product ion
corresponds to either the amidate complex [(phen)Pd(NPhC-
(O)Ph)]+ or the isocyanate adduct [(phen)Pd(PhNCO)-
(Ph)]+. The CID spectrum of this product ion is very similar to
that of palladium benzamidate, prepared by mixing N-
phenylbenzamide, palladium trifluoroacetate, and phen in
methanol (Figure S5b).24 Both CID processes proceed via
two different fragmentation channels: (a) loss of phenyl
isocyanate to re-form the organometallic ion 6 as the major
pathway (Figure 1c and eq 8) and (b) loss of benzene to
produce an ion at m/z 404 as a minor pathway (Figure 1c and
eq 9). Deuterium labeling studies in which CID of the product
formed by the IMR of [(phen)Pd(C6D5)]+ and phenyl
isocyanate proceeded via loss of C6D5H (Figure S6) confirm
that arene loss originates from the benzoic acid and not the
phenyl isocyanate.
Scheme 3. General Mechanism for Extrusion of CO2 as in
a
Eq 6
a
Specific systems studied: (a) N−N = phen and Ar = C6H5 (ref 9);
(b) N−N = phen and Ar = 2,6-(CH3O)2C6H3 (ref 10); (c) N−N =
bpy and Ar = C6H5 (this work); (d) N−N = bpy and Ar = 2,6-
(CH3O)2C6H3 (this work); (e) N−N = 6mbpy and Ar = C6H5 (this
work); (f) N−N = 6mbpy and Ar = 2,6-(CH3O)2C6H3 (this work).
[(phen)Pd(NRC(O)Ar)]+ → [(phen)Pd(Ar)]+ + RNCO
(8)
[(phen)Pd(NRC(O)Ar)]+ → [(phen)Pd((RNCO)‐H)]+ + ArH
(9)
Table 1. DFT Data of Relative Gibbs Energies and Enthalpies (In Parentheses) Given in kcal/mol for the Species Associated
with Extrusion of CO2 Shown in Scheme 3 (Eq 6)
system
6
TS6-7
7
TS7-8
8
9
a
(a) [(phen)Pd(C6H5)]+
0.0 (0.0)
0.0 (0.0)
0.0 (0.0)
0.0 (0.0)
34.9 (35.1)
35.9 (34.4)
36.2 (35.2)
37.1 (35.2)
15.3 (15.2)
4.0 (4.0)
17.8 (16.0)
5.4 (4.7)
27.1 (27.9)
12.0 (10.1)
26.9 (27.1)
11.3 (11.6)
9.3 (12.0)
0.1 (1.8)
9.5 (12.4)
2.7 (3.6)
b
c
(b) [(phen)Pd((CH3O)2C6H3)]+
(c) [(bpy)Pd(C6H5)]+
(d) [(bpy)Pd((CH3O)2C6H3)]+
4.9 (16.6)
13.4 (25.9)
6.8 (18.6)
a
b
c
From ref 9. Not calculated. From ref 10.
C
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Figure 2. DFT calculated energy surface for reaction of [(phen)Pd(C6H5)]+ (9a) with phenyl isocyanate (eq 7). The relative Gibbs energies and
enthalpies (in parentheses) are given in kcal/mol and were calculated at the B3LYP-D3BJ/BS2//M06/BS1 level of theory.
Table 3. DFT Data of Relative Gibbs Energies and Enthalpies (in Parentheses) Given in kcal/mol for the Species in the
Insertion Reactions of [(L)Pd(C6H5)]+ and Phenyl Isocyanate
system
coordination mode
9
10
TS10-11
11
12
(a) [(phen)Pd(C6H5)]+
Pd−O
Pd−N
Pd−O
Pd−N
0.0 (0.0)
0.0 (0.0)
0.0 (0.0)
0.0 (0.0)
−13.4 (−25.8)
−14.9 (−28.3)
−12.7 (−26.0)
−17.3 (−29.6)
13.7 (−1.3)
−4.1 (−18.2)
12.1 (−2.3)
−3.3 (−18.6)
−4.3 (−20.0)
−15.0 (−33.0)
−5.9 (−21.3)
−16.3 (−31.6)
−28.5 (−44.7)
−28.5 (−44.7)
−30.9 (−46.5)
−30.9 (−46.5)
(c) [(bpy)Pd(C6H5)]+
Both 9c and 9e react more readily with phenyl isocyanate
(9.6 × 10−10 and 2.4 × 10−10 cm3 molecules−1 s−1,
respectively). These reactions are notably more efficient
(79% and 20%, respectively) than the reaction starting from
9a (8%), indicating a lower barrier for phenyl isocyanate
insertion in the bpy-ligated complexes relative to the phen-
ligated complex. There is no reaction with phenyl isocyanate
when we replaced benzoic acid (systems a, c, and e) with 2,6-
dimethoxybenzoic acid (systems b, d, and f) (Table 2).
DFT calculations on the insertion step (Figure 2) predict
the reaction of [(phen)Pd(C6H5)]+ (9a) and phenyl
isocyanate to initially afford the N-coordinated phenyl
isocyanate adduct (10a-N). Binding of the phenyl isocyanate
via the oxygen (10a) is both kinetically and thermodynamically
less favorable (Table 3). Subsequent C−C bond formation via
transition structure TS10c-11c-N affords the κ2-N,C-benzami-
date complex (11a-N). The energy of transition structure
TS10c-11c-N lies below that of the starting reagents,
indicating that C−C bond formation is kinetically accessible
under ion−molecule reaction conditions, supporting our
earlier assignment of the product ion as an amidate complex
rather than an isocyanate adduct. Structure 11a-N sub-
sequently isomerizes to the more stable κ2-N,O-benzamidate
structure (12a). This mode of amidate binding to palladium
has precedence in other structurally characterized group 10
complexes.25,26 The overall reaction of 9a with phenyl
isocyanate to afford 12a is predicted to be highly exothermic
and exergonic. With bpy ligation, an analogous mechanism is
computed (Figure S7). However, lower barriers are calculated
relative to the phen-ligated system, consistent with the
experimentally determined relative reaction efficiencies
(Table 3). DFT calculations also predict lower kinetic barriers
for the phenyl isocyanate insertion into the methoxy-
substituted intermediates 9b,d (Figures S8 and S9). However,
in both cases lower energy isomers of 9b and 9d are located,
where one of the o-methoxy substituents binds to the vacant
site on palladium, cf. 9b2,d2 (Figures S8 and S9), thereby
blocking coordination of phenyl isocyanate. These results are
consistent with the poor reactivity observed experimentally for
these systems (Table 2).
Competition between Isocyanate and Arene Loss in
the CID Reactions of Amidate Complexes [(phen)Pd-
(NRC(O)Ar)]+. Given that the CID spectra of the authentic
amidate complexes show two competing fragmentation
D
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Figure 3. DFT calculated energy surface for fragmentation of [(phen)Pd(NPhC(O)Ph)]+ (12a): deinsertion of PhNCO (eq 8) and loss of
benzene from C−H bond activation (eq 7). The relative Gibbs and enthalpy energies (in parentheses) are given in kcal/mol and were calculated at
the B3LYP-D3BJ/BS2//M06/BS1 level of theory.
Scheme 4. Scope of Stoichiometric Palladium-Mediated Decarboxylative Synthesis of Benzamides in Terms of the Isocyanate
Substrates Used
channels (eqs 8 and 9), we decided to probe their mechanisms
via DFT calculations. The calculated fragmentation pathways
starting from the κ2-N,O-benzamidate structure, 12a, are
shown in Figure 3. Under the experimental low-energy CID
conditions, the fragmentation reactions are under kinetic
control and entropic effects play a role. While the exact
temperature of the fragmenting ions is unknown, we use the
DFT calculated Gibbs free energies at 298 K as the key
thermochemical parameter when considering competing
fragmentation pathways. Thus, while the loss of benzene
rather than isocyanate is predicted to be thermodynamically
favored by 8 kcal/mol, the benzene elimination pathway
proceeds through a high barrier, TS13a-14a, making loss of
phenyl isocyanate the kinetically favored pathway, consistent
with the experimental outcome (Figure 1c).
Condensed-Phase Studies To Isolate Amides and
Explore Substrate Scope Using Stoichiometric Pd Salts
under Ligand-Free Conditions. Encouraged by the proof of
concept gas-phase studies, we explored the conversion of 2,6-
disubstituted benzoic acids into benzamides using a stoichio-
metric amount of palladium trifluoroacetate. Employing the
conditions previously optimized for synthesis of amidines, 2,6-
dimethoxybenzoic acid was decarboxylated by palladium
trifluoroacetate in DMSO at 70 °C for 4 h (Scheme 4).
Subsequent addition of excess phenyl isocyanate at room
temperature and protodemetalation with formic acid afforded
N-phenyl-2,6-dimethoxybenzamide (5-Ph), as identified by
HRMS of the crude reaction mixture. This compound was
separated from the side products, 1,3-diphenylurea27 and 1,3-
dimethoxybenzene,28 by column chromatography and isolated
in good yield (Scheme 4). With the optimized reaction
conditions in hand, we explored the scope of possible
substrates with an electron-withdrawing aryl isocyanate, 4-
(trifluoromethyl)phenyl isocyanate. The resultant amide, 5-
CF3Ph, was obtained in good yield (Scheme 4). Aliphatic
isocyanates were also investigated and led to isolation of
benzamide product in moderate to good yield (Scheme 4),
with the exception of 1-adamantyl isocyanate. Interrogation of
the crude reaction mixture revealed significant quantities of the
protodecarboxylation side product (eq 10), formed via
protonation of the organopalladium species (eq 11, where L
= DMSO, X = CF3CO2, and HA = CF3CO2H),28 accompanied
by 1-adamantylamine, as determined by GCMS and HRMS,
respectively (data not shown). This is consistent with our
E
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previous isothiocyanate insertion chemistry, where sterically
demanding heterocumulenes were found to insert slowly,
thereby promoting the undesired protodecarboxylation side
reaction.9
product relative to the desired insertion product (the relative
ratio is 1:25, data not shown) on the basis of a comparison of
the integrated areas associated with the resonances at 6.52 ppm
(due to the 4,6-protons of 1,3-dimethoxybenzene) and 6.65
ppm (due to the 3,5-protons of 5-Et) in an expanded Figure
5c.
ArCO2H → ArH + CO2
(10)
DFT Calculations of Elementary Steps under Ligand-
Free Conditions. The ligand-free palladium-mediated de-
carboxylation of o-methoxy-substituted benzoic acids in
DMSO has been extensively studied experimentally28,30 and
theoretically.31,32 We therefore focused specifically on the
isocyanate coordination and insertion steps using DFT
calculations, as our initial gas-phase model did not capture
the absence of ligands and solvent molecules. Previously,10 we
have shown that the identity of the acid reservoir formed as a
byproduct in the first step in solution (eq 2 in Scheme 2 to
form either acetic acid or trifluoroacetic acid (TFA)), has an
important effect on the barriers to insertion of a carbodiimide
and the competitive protodecarboxylation. The presence of
TFA was found to disfavor the protodecarboxylation (eqs 10
and 11) pathway relative to acetic acid, resulting in a more
productive ExIn reaction.
[(L)nPd(Ar)(X)] + HA → [(L)nPd(A)(X)] + ArH
(11)
All isolated benzamides were characterized by HRMS and
1H and 13C{1H} NMR spectroscopy (Figures S10−S21).
Additionally, several benzamides (Figures S22−S24 and Table
S1) were structurally characterized by X-ray crystallography
(Figure 4). The crystalline amides are present as the E
Insertion Reaction of Ethyl Isocyanate with the Organo-
palladium Intermediate. Here we focus on the insertion of
ethyl isocyanate into the Pd−C bond of the trifluoroacetate-
coordinated organopalladium complex 17g, (eq 4 of Scheme 1
and Figure 6). Insertion starts with a simple associative
displacement of one of the coordinating O donor atoms of the
bidentate trifluoroacetate ligand by the nitrogen of the
isocyanate via transition structure TS17g-18g-N to give the
coordination complex 18g-N. This is followed by the
migratory insertion of isocyanate into the Pd−Ar bond to
afford 19g-N. An alternative pathway, involving initial
coordination of the isocyanate by the oxygen atom, affords a
much higher energy surface (Figure S25). The key barrier for
insertion of ethyl isocyanate (TS17g-18g-N, 16.1 kcal/mol) is
considerably lower than the experimentally determined barrier
(ΔG⧧ = 27 kcal/mol) for the undesired protonation (eq 11) to
give the 1,3-dimethoxybenzene protodecarboxylation side
product.28 This is consistent with the mild conditions under
which migratory insertion of ethyl isocyanate occurs (Scheme
4) and is thus also consistent with the high selectivity for
benzamide formation over protodecarboxylation (Scheme 4
and Figure 5).
Demetalation of the Coordinated Amidate. A key
difference in the ligand-free stoichiometric one-pot ExIn
synthesis of benzamides in comparison to those of thioamides
and amidines is that exogenous hydrogen sources were
required to release the thioamides and amidines from the
metal ion. This suggests that the amidate binds less strongly to
the Pd ion than the carboxylate,33 whereas the thioamides and
amidines bind more strongly.34 Since there is a dearth of
experimental thermodynamic data on binding energies of these
anions to Pd centers, DFT calculations were used to investigate
the overall energetics for demetalation of 19g-N and the
related thioamidate and amidinate complexes by TFA to return
to the starting [(DMSO)nPd(O2CCF3)2] complex (Table 4).
Release of the benzamide via protonation by TFA is exergonic,
while for thioamides and amidines the reactions are not
thermodynamically favored. These data explain why an
exogenous hydrogen source is not required to release the
benzamide from the metal but is required to release related
thioamides and amidines.
Figure 4. Representation (50% displacement ellipsoids) of the solid-
state packing found in the X-ray crystal structure of 5-Cy. All
hydrogen atoms except for the amide hydrogen are omitted for clarity.
Symmetry operation used to generate atoms: (′) 1 − x, 1/2 + y, 3/2
− z.
conformer, affording one-dimensional polymeric chains. This is
in contrast with the aggregation observed for the analogous
thioamides we reported previously, where the Z conformer is
exclusively observed, resulting in weakly dimeric structures due
to short intermolecular N−H···S contacts.9 In this instance, the
2,6-dimethoxy groups on the benzamide prevent rotation of
the phenyl plane, resulting in a much larger N1−C1−C2−C3
torsion angle (−71.0(4)°) relative to that in N-cyclo-
hexylbenzamide (−30.8(4)°).29
Condensed-Phase Mechanistic Studies under Li-
gand-Free Conditions Using Stoichiometric Pd Salts.
To further probe whether the “ExIn” mechanism is operating
in the condensed phase (eqs 3−5, Scheme 2), we have
monitored the transformation of 2,6-dimethoxybenzoic acid to
5-Et by analyzing aliquots of reaction mixtures using 1H NMR
spectroscopy. The organometallic intermediate, tentatively
assigned as [(DMSO)nPd(O2CCF3)(Ar)] (3), was generated
from [(DMSO)nPd(O2CCF3)(O2CAr)] (2) as previously
described (Figure 5a).9,10,28 Upon addition of ethyl isocyanate
at room temperature, the resonance attributed to the Hpara
proton shifts downfield by 0.16 ppm, likely due to the insertion
of the isocyanate, affording an amidate complex (Figure 5b).
No major chemical shift changes for these resonances were
observed upon addition of formic acid (Figure 5c). In fact,
these resonances (Figure 5b) are identical with those of the
isolated and purified amide (Figure 5d). This indicates that the
amidate complex 5-Et undergoes rapid protodemetalation in
the absence of an exogenous hydrogen source. It is important
to highlight that 1,3-dimethoxybenzene is only a minor side
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Figure 5. Pd(O2CCF3)2-induced transformation of 2,6-dimethoxybenzoic acid to benzamide monitored by 1H NMR spectroscopy (600 MHz) in
DMSO-d6 (only the resonances due to the aromatic protons are shown): (a) decarboxylation of benzoate palladium complex for 4 h; (b) insertion
of ethyl isocyanate into the Pd−C bond after 2 h; (c) addition of formic acid to the mixture; (d) purified benzamide product (5-Et) measured at
400 MHz. The arrows in (a) and (b) are used to show the change in chemical shift during the transformation.
Solution-Phase Experiments: Palladium-Catalyzed
Amide Synthesis Activated by a Microwave Reactor.
The NMR experiments indicate rapid protonation of the
intermediate amidate complex in the absence of exogenous
acid, suggesting the potential for this “ExIn” reaction to
proceed with a catalytic quantity of Pd(O2CCF3)2. The
reaction of 2,6-dimethoxybenzoic acid with cyclohexyl
isocyanate in DMSO with Pd(O2CCF3)2 (5 mol %) followed
by microwave irradiation35 at 130 °C for 30 min was
investigated by 1H NMR analysis of the crude reaction mixture
and indicated the formation of 5-Cy in 22% yield (Table 5,
entry 1). Larhed previously developed a decarboxylative
Pd(O2CCF3)2 catalyzed synthesis of aryl amidines from
2,4,6-trimethoxybenzoic acid and aryl trifluoroborates.36,37 In
that study, the combination of 6-methyl-2,2′-bipyridyl
(6mbpy) as the ligand and N-methylpyrrolidinone (NMP) as
the solvent were found to greatly enhance the product yield.
Repeating the reaction in NMP with a ligand loading of 7.5%
afforded 5-Cy in good yield (Table 5, entry 2). Next, we
conducted a screening of solvents (Table 5). The performance
of DMSO and dimethylformamide (DMF) is similar to that of
NMP (Table 5, entries 3 and 4), while dimethylacetamide
(DMA) and cyrene38 performed poorly (Table 5, entries 5 and
6). It is noteworthy that a control experiment performed with
the addition of TFA (Table 5, entry 7) afforded an inferior
yield; clearly a lower concentration of TFA is crucial for a
productive ExIn reaction in comparison with the proto-
decarboxylation side reaction (eqs 10 and 11).28,39
Having identified NMP as the solvent of choice, the effect of
using different ligands was investigated (Table 6). The 6mbpy
ligand used in the test reaction was found to perform the best.
Symmetrically substituted bpy and phen ligands all displayed
significantly inferior performance. These outcomes mirror
those reported for the decarboxylative synthesis of aryl
amidines.36 In the current work, the main reason for the
poorer performance is an increase in the formation of the 1,3-
dimethoxybenzene side product (eqs 10 and 11), on the basis
1
of the H NMR spectra of the crude reaction mixtures (data
not shown).
The use of different substituted isocyanates was also
investigated (Scheme 5). Both aliphatic and aryl isocyanates
afford the corresponding benzamides 5 in good yields. When
2,4,6-trimethoxybenzoic acid was employed instead of 2,6-
dimethoxybenzoic acid, the corresponding benzamides 5b
(Figures S26−S36 and Table S3) were obtained but in lower
yields. Nonetheless, these yields are significantly better than
those reported for trimethoxybenzamides developed as
selective P-glycoprotein inhibitors and prepared from the
reaction of the benzoic acid with thionyl chloride followed by
the reaction of the resultant acid chloride with aniline.14
Previously, we observed deinsertion of phenyl isocyanate as
the major fragmentation channel for ligated palladium amidate
cations in the gas phase (Figure 1c). Indeed, there are several
reports of the deinsertion of aryl isocyanates from a late-
transition-metal benzamidate complex in solution.11,40 We
became intrigued as to whether protodemetalation and C−C
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Figure 6. DFT calculated energy surface showing insertion of ethyl isocyanate into [(L)nPd(Ar)] (17g). The relative Gibbs energies and enthalpies
(in parentheses) are given in kcal/mol and were calculated at the B3LYP-D3BJ/BS2//M06/BS1 level of theory in DMSO using the CPCM
approach.
Table 4. Calculated Gibbs Free Energies and Enthalpies for the Protodemetalation of Palladium Benzamidate, Thioamidate,
and Amidinate Complexes by TFA in DMSO
system
Y
Z
ΔG (kcal/mol)
ΔH (kcal/mol)
this work
ref 7
ref 9
O
S
N(C2H5)
N(CH3)
N(CH(CH3)2)
−1.2
17.5
15.9
5.5
25.0
23.5
N(CH(CH3)2)
bond formation were reversible under the catalytic regime. To
this end, we first performed a crossover experiment: 5-Ph and
cyclohexyl isocyanate (4 equiv) were subjected to the catalytic
regime (Scheme 6). Interrogation of the reaction crude by
GCMS and HRMS revealed the formation of trace amounts of
5-Cy (m/z 264.16, Figure S37a). The detection of 1-
cyclohexyl-3-phenylurea further supports the extrusion of
phenyl isocyanate (m/z 219.15, Figure S37a). Similarly,
subjecting 5-Cy and phenyl isocyanate (4 equiv) to the
catalytic regime afforded 5-Ph (m/z 258.11, Figure S37b) in
ca. 5% yield on the basis of analysis by GCMS (Scheme 6)
(Figure S37c). DFT calculations indicate that the free energy
changes for these reactions are negligible; hence, the outcomes
of these reactions signal kinetic barriers for benzamide
deprotonation or isocyanate extrusion. A similar control
reaction revealed that the undesired protonation of the
organopalladium intermediate (eq 11) is irreversible under
the catalytic regime.
dium, and Protodecarboxylation of the 6-Methyl-2,2′-
bipyridyl Aryl Palladium Intermediate. The role of the
ligand 6mbpy on the competing insertion and protodecarbox-
ylation pathways (eq 3, Scheme 2) was probed by DFT
calculations. We first modeled the insertion of ligated
palladium complexes in the solution phase (Figure 7, right).
In this instance the ground state for the reaction was found to
be a four-coordinate palladium complex ligated by a molecule
of NMP, 17f. Associative substitution of the solvent molecule
by ethyl isocyanate via TS17f-18f is rate-determining for the
C−C bond formation pathway. Protodecarboxylation (Figure
7, left) proceeds through a notably higher barrier, TS21f-22f,
which is a five-coordinate transition structure en route to the
proton being delivered by the coordinated TFA.41 The κ2-N,O-
benzamidate complex 20f is also the slightly favored
thermodynamic product.
To complete the catalytic cycle, the process of proto-
demetalation starting from the κ2-N,C-benzamidate palladium
complex 19f42 to regenerate the benzoate-coordinated
palladium complex 6 was probed using DFT calculations
DFT Calculations on the Competition among In-
sertion of Isocyanate, Protonation of Amidate Palla-
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occur rapidly relative to the nonproductive protodecarbox-
ylation pathway (eqs 10 and 11).
Table 5. Additive and Solvent Screening
These mechanistic studies and our previous work allow the
proposal of a plausible catalytic cycle (Figure 9). The initial
benzoate complex 2 undergoes decarboxylation to afford the
arylpalladium complex 3. Coordination of the isocyanate,
followed by migratory insertion, forms the C−C bond and
produces the key benzamidate intermediate 4′. Subsequent
protodemetalation by benzoic acid, mediated by trifluoroace-
tate, releases the benzamide and closes the catalytic cycle.
CONCLUSIONS
■
We have used a mechanistic-based approach that blends
fundamental gas-phase ion chemistry, condensed-phase stoi-
chiometric reactions, and DFT calculations to study the
palladium-mediated conversion of aromatic carboxylic acids to
benzamides via the isohypsic “ExIn” reaction sequence. A key
finding is that protodemetalation of the benzamidate
intermediate is thermodynamically favorable in comparison
to previous “ExIn” systems where an exogenous hydrogen
source was needed to release the product from the metal.
These fundamental studies enabled a microwave irradiation
assisted protocol to be developed, which affords o-methoxy-
substituted benzamides in moderate to good yields, employing
catalytic amounts of palladium(II). This approach represents a
significant improvement on the current methods to prepare o-
methoxy-substituted benzamides, which either are low yielding
or suffer poor atom economy. We are currently exploring the
use of other metals and ligands to extend the scope of amide
synthesis via ExIn reactions to include a wider range of
aromatic carboxylic acids.
a
1
Calculated yields of product using H NMR spectroscopic analysis
b
with a known internal standard; With TFA (2 equiv).
Table 6. Ligand Screening
EXPERIMENTAL METHODS
■
Gas-Phase Experiments. Sample Preparation. The gas-phase
collision-induced dissociation (CID) of [(L)Pd(O2CR)]+ to form
[(L)Pd(R)]+ and subsequent ion−molecule reaction studies were
conducted in a similar manner to those reported for the reactivity
studies of [(phen)M(CH3)]+.43−45 For example, 10 μL of methanolic
solutions of palladium salt (5 mM), benzoic acid (10 mM), and ligand
(10 mM) were mixed and then diluted to a final concentration of 0.05
mM in metal. The solution was transferred via syringe pump
operating at 5 μL min−1 to the electrospray ionization source of a
Thermo Finnigan LTQ ESI mass spectrometer previously modified to
allow the introduction of neutral reagents into the ion trap.46,47 Data
were collected with three microscans and between 20 and 100
duplicate spectra.
Mass Spectrometry Source Conditions. Typical electrospray
source conditions were as follows.
Collision-induced dissociation (CID): sheath gas, 10 arbitrary
units; auxiliary gas, 5 arbitrary units; sweep gas, 0 arbitrary units; spray
voltage, 4 kV; capillary temperature, 250 °C; capillary voltage, 2 V;
tube lens voltage, 75 V. The precursor ion was mass-selected with a
window of 1 m/z, and collision-induced dissociation was carried out
using the helium bath gas by activating the ion with an activation time
of 30 ms. A normalized collision energy (NCE) was chosen to deplete
the precursor ion to 10%.
Ion−molecule reaction (IMR): sheath gas, 10 arbitrary units;
auxiliary gas, 5 arbitrary units; sweep gas, 0 arbitrary units; spray
voltage, 4 kV; capillary temperature, 250 °C; capillary voltage, 2 V;
tube lens voltage, 75 V.
Solution-Phase Experiments. General Methods. Unless other-
wise stated, all reagents were purchased from commercial sources and
used without further purification. Flash column chromatography was
carried out using Davisil Chromatographic Silica Media (40−63 μm,
with solvent systems as specified) at the stationary phase.
a
1
Calculated yields of product using H NMR spectroscopic analysis
with a known internal standard.
(Figure 8). The key transition state, TS24f-25f, where the
proton is transferred from the TFA to the oxygen atom of the
benzamidate, lies 2 kcal/mol lower than the rate-determining
step on the protodecarboxylation pathway (TS21f-22f, 11.8
kcal/mol). This result is consistent with the experimental
finding that isocyanate insertion and protodemetalation can
I
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Scheme 5. Scope of the “ExIn” Reaction with Regard to the Isocyanates and Substituted Benzoic Acids
Scheme 6. Reversibility of Protodemetallation and C−C Bond Formation
Figure 7. DFT calculated energy surface showing protonation (left) and insertion (right) of ethyl isocyanate into [(6Mebpy)Pd(Ar)]+ (16f). The
relative Gibbs energies and enthalpies (in parentheses) are given in kcal/mol and were calculated at the B3LYP-D3BJ/BS2//M06/BS1 level of
theory in DMA using the CPCM approach.
1H NMR and 13C{1H} NMR spectra were recorded either on a 600
MHz Varian/Agilent 600-MR or 400 MHz Varian/INOVA 400-AR
spectrometer at 298 K. Chemical shifts are reported in parts per
million (ppm) and referenced to the residual solvent peak (DMSO-
collected on a Thermo Scientific Exactive Plus Orbitrap mass
spectrometer (Thermo, Bremen, Germany).
1H NMR Monitoring Experiment. A round-bottom flask was
charged with 2,6-dimethoxybenzoic acid (0.2 mmol) and palladium-
(II) trifluoroacetate (0.22 mmol) under N2. DMSO-d6 (2 mL) was
added under N2, and the mixture was stirred for 5 min at room
temperature. For all sequential 1H NMR experiments used to monitor
reaction outcomes, a 50 μL aliquot of the reaction mixture was
withdrawn from the sample tube, transferred to an NMR tube, and
1
d6: H NMR 2.50 ppm, 13C NMR 39.52 ppm). Coupling constants
(J) are reported in Hertz (Hz). Standard abbreviations indicating
multiplicity were used as follows: m = multiplet, quint = quintet, q =
quartet, t = triplet, d = doublet, s = singlet, br = broad. High-
resolution electrospray ionization mass spectra (ESI- HRMS) were
J
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Figure 8. DFT calculated energy surface showing protonation of [(6Mebpy)Pd(NEtC(O)Ar)]+. The relative Gibbs energies and enthalpies (in
parentheses) are given in kcal/mol and were calculated at the B3LYP-D3BJ/BS2//M06/BS1 level of theory in DMA using the CPCM approach.
completely consumed. Formic acid (10 equiv) was then added to the
solution and stirred for a further 1 h at room temperature. A final 1H
NMR spectrum of the reaction mixture was recorded. The recorded
spectra were stacked, including the spectrum of pure product, and are
shown in Figure 5. ESI/HRMS analyses was conducted on the final
NMR sample by diluting in methanol.
General Experimental Procedures in the Solution Phase.
One-Pot Synthesis Using Ligand-Free Stoichiometric Palladium(II)
Trifluoroacetate. To a solution of 2,6-dimethoxybenzoic acid (0.5
mmol, 1 equiv) in DMSO (5 mL) was added palladium(II)
trifluoroacetate (0.55 mmol, 1.1 equiv). The mixture was heated
under N2 at 70 °C for 4 h and then cooled to room temperature.
RNCO (1 mmol, 2.0 equiv) was added, and the mixture was then
stirred for 2 h at room temperature. Formic acid (5 mmol, 10 equiv)
was then added and the reaction mixture was stirred for an additional
1 h at room temperature. Methanol (5 mL) was added to the mixture
followed by water (100 mL), and the aqueous layer was extracted with
ethyl acetate (3 × 50 mL). The combined organic fractions were
washed with water (100 mL) and brine (100 mL) and dried over
anhydrous Na2SO4. The solvent was removed using a rotary
evaporator, and the residue was purified by column chromatography
to give amides 5.
Microwave Method Using Catalytic Loading of Palladium(II)
Trifluoroacetate with the 6-Methyl-2,2′-bipyridyl Ligand.
Figure 9. Proposed catalytic cycle for the decarboxylative synthesis of
Palladium(II) trifluoroacetate (0.025 mmol, 5 mol %), 6-methyl-
benzamides.
2,2′-bipyridyl (0.0375 mmol, 7.5 mol %), and NMP (1.5 mL) were
placed in a 0.5−2 mL process vial, and the mixture was stirred for 2
1
min before 2,6-dimethoxybenzoic acid or 2,4,6-trimethoxybenzoic
acid (0.5 mmol, 1 equiv) and isocyanate (1.0 mmol, 2 equiv) were
added. The vial was instantly capped under air and then heated by
using microwave irradiation at 130 °C for 30 min. Methanol (5 mL)
was added to the mixture followed by water (100 mL), and the
aqueous layer was extracted with ethyl acetate (3 × 50 mL). The
combined organic layers were washed with water (100 mL) and brine
diluted with 600 μL of DMSO-d6 and then a H NMR spectrum was
collected. The mixture was then warmed to 70 °C for 4 h. H NMR
spectra were recorded hourly, and the formation of an aryl palladium
species was confirmed by the appearance of a new upfield-shifted set
of aromatic peaks. The mixture was cooled to room temperature.
Ethyl isocyanate (2 equiv) was added, and then a 1H NMR spectrum
was collected hourly until the aryl palladium intermediate was
1
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(100 mL) and dried over anhydrous Na2SO4. The solvent was
removed using a rotary evaporator, and the residue was purified by
column chromatography to give the benzamides 5.
DMSO-d6): δ 10.45 (s, 1H), 7.88 (d, J = 8.4 Hz, 2H), 7.64 (d, J = 8.5
Hz, 2H), 6.28 (s, 2H), 3.80 (s, 3H), 3.73 (s, 6H). 13C{1H} NMR
(100 MHz, DMSO-d6): δ 164.45, 162.24, 158.17, 143.67, 126.40,
123.62, 123.31, 119.20, 109.98, 91.29, 56.25, 56.00. HR-ESMS (ESI):
m/z [M + H]+ calcd for C15H21NO3 356.11042, found 356.11085.
X-ray Crystallography. Single-crystal X-ray diffraction data for all
samples were collected as follows: a typical crystal was mounted on a
MiTeGen Micromount using high-viscosity oil and cooled rapidly to
100(2) K under a stream of nitrogen gas using an Oxford Cryostream
cooling device. Diffraction data were collected (ω scans) on a Rigaku
XtaLAB Synergy or Synergy-S diffractometer equipped with a Hypix
detector using Cu Kα radiation (λ= 1.54184 Å). Raw frame data were
reduced using CrysAlisPro. The structures were solved using
SHELXT,48 and the refinement was carried out with SHELXL
(version 2018/3)49 employing full-matrix least squares on F2 using the
OLEX2 software packages.50 All non-hydrogen atoms were refined
anisotropically. The hydrogen atoms were placed in geometrically
calculated positions and refined using a riding model. Selected
crystallographic data and comments about individual crystal structures
can be found in the Supporting Information.
N-Ethyl-2,6-dimethoxybenzamide (5-Et). This compound was
prepared using both the one-pot method and microwave method:
yield 53 mg (51%) white solid for the one-pot method; 73 mg (70%)
for the microwave method. Column chromatography (silica gel,
methanol/DCM 1/50). 1H NMR (400 MHz, DMSO-d6): δ 7.92 (t, J
= 5.6 Hz, 1H), 7.24 (t, 1H), 6.63 (d, J = 8.3 Hz, 2H), 3.70 (t, 6H)
3.17−3.10 (m, 2H), 1.03 (s, 3H). 13C{1H} NMR (100 MHz, DMSO-
d6): δ 164.60, 157.11, 130.17, 117.63, 104.64, 56.14, 34.03, 15.04.
HR-ESMS (ESI): m/z [M + H]+ calcd for C15H21NO3 210.11247,
found 210.11257.
N-Cyclohexyl-2,6-dimethoxybenzamide (5-Cy). This compound
was prepared using both the one-pot method and microwave method:
yield 105 mg (80%) white solid for the one-pot method; 100 mg
(76%) for the microwave method. Column chromatography (silica
gel, methanol/DCM 1/50). 1H NMR (400 MHz, DMSO-d6): δ 7.80
(d, J = 8.1 Hz, 1H), 7.23 (t, J = 8.3 Hz, 1H), 6.62 (d, J = 8.4 Hz, 2H),
3.69 (s, 6H), 3.62 (dt, J = 7.0, 3.2 Hz, 1H), 1.77−1.51 (m, 5H),
1.27−1.07 (m, 5H). 13C{1H} NMR (100 MHz, DMSO-d6): δ 164.13,
157.11, 130.19, 117.62, 104.71, 56.19, 48.29, 32.68, 25.68, 25.05. HR-
ESMS (ESI): m/z [M + H]+ calcd for C15H21NO3 264.15942, found
264.15905
N-Phenyl-2,6-dimethoxybenzamide (5-Ph). This compound was
prepared using both the one-pot method and microwave method:
yield 100 mg (78%) white solid for the one-pot method; 116 mg
(90%) for the microwave method. Column chromatography (silica
gel, ethyl acetate/petroleum ether 1/3), white solid (100 mg, 78%).
1H NMR (400 MHz, DMSO-d6): δ 10.14 (s, 1H), 7.67 (d, 2H), 7.31
(t, J = 8.4 Hz, 1H), 7.26 (t, J = 7.9 Hz, 2H), 7.01 (t, J = 7.4 Hz, 1H),
6.69 (d, J = 8.4 Hz, 2H), 3.72 (s, 6H). 13C{1H} NMR (100 MHz,
DMSO-d6): δ 163.77, 157.15, 140.12, 130.78, 129.06, 123.51, 119.35,
117.35, 104.69, 56.22. HR-ESMS (ESI): m/z [M + H]+ calcd for
C15H21NO3 258.11247, found 258.11215. Spectroscopic data are
consistent with the literature reported data.9
N-(4-(Trifluoromethyl)phenyl)-2,6-dimethoxybenzamide (5-
CF3Ph). This compound was prepared using both the one-pot
method and microwave method: yield 109 mg (67%) white solid for
the one-pot method; 149 mg (92%) for the microwave method.
Column chromatography (silica gel, ethyl acetate/petroleum ether 1/
3). 1H NMR (400 MHz, DMSO-d6): δ 10.56 (s, 1H), 7.88 (d, J = 8.5
Hz, 2H), 7.65 (d, J = 8.6 Hz, 2H), 7.35 (t, J = 8.4 Hz, 1H), 6.73 (d, J
= 8.4 Hz, 2H), 3.74 (s, 6H). 13C{1H} NMR (100 MHz, DMSO-d6): δ
164.47, 157.17, 143.50, 131.16, 126.49, 126.45, 123.78, 119.30,
118.57, 116.76, 104.72, 56.28. HR-ESMS (ESI): m/z [M + H]+ calcd
for C15H21NO3 326.09985, found 326.09994.
N-Cyclohexyl-2,4,6-trimethoxybenzamide (5b-Cy). This com-
pound was prepared using the microwave method: yield 63 mg
(43%) as a white solid. Column chromatography (silica gel,
methanol/DCM 1/50). 1H NMR (400 MHz, DMSO-d6): δ 7.66
(d, J = 8.1 Hz, 1H), 6.18 (s, 2H), 3.75 (s, 3H), 3.68 (s, 6H), 3.60 (dt,
J = 7.0, 3.2 Hz, 1H), 1.72−1.47 (m, 5H), 1.22−1.03 (m, 5H).
13C{1H} NMR (100 MHz, DMSO-d6): δ 163.92, 161.41, 158.01,
DFT Calculations. Gaussian 0951 was used to fully optimize all
structures at the M06 level of density functional theory (DFT).52 The
effective-core potential of Hay and Wadt with a double-ξ valence basis
set (LANL2DZ) was chosen to describe Pd.53,54 The 6-31G(d) basis
set was used for other atoms.55 A polarization function of ξf = 1.472
was also added for Pd.56,57 This basis set combination will be referred
to as BS1. Solvation effects of DMSO on the optimized structures
were accounted for using the CPCM model.58 Frequency calculations
were carried out at the same level of theory as those for the structural
optimization. Transition structures were located using the Berny
algorithm. Intrinsic reaction coordinate (IRC) calculations were used
to confirm the connectivity between transition structures and minima.
To further refine the energies obtained from the M06/BS1
calculations, we carried out single-point energy calculations for all of
the structures with a larger basis set (BS2) at the B3LYP-D3BJ level of
theory.59−62 BS2 utilizes def2-TZVP11 for all atoms along with the
effective core potential including scalar relativistic effects for Pd.63
The solvent effect using the CPCM approach was considered for the
DMSO or DMF (as an analogue of NMP) system in the single-point
calculations. The B3LYP-D3BJ calculations were used to overcome
the deficiency of the M06 level in incorporating long-range correlation
for dispersion forces. To estimate the corresponding enthalpy, ΔH,
and Gibbs energies, ΔG, the corrections were calculated at the M06/
BS1 levels and finally added to the corresponding single-point
energies. Entropy calculations for the solvent system were adjusted by
the method proposed by Okuno.64 An additional correction was made
to account for the fact that DMSO or NMP participates in the
equilibrium. Thus, when the energy profiles for Figures 6−8 were
calculated, the concentration of the solvent was set using the method
of Keith and Carter (we utilized eq 6 of their paper).65 We have used
the corrected enthalpy and Gibbs free energies obtained from the
B3LYP-D3BJ/BS2//M06/BS1 calculations throughout unless other-
wise stated.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.organomet.9b00820.
157.05, 91.32, 56.16, 55.83, 48.24, 33.80, 32.74, 25.77, 25.09. HR-
ESMS (ESI): m/z [M + H]+ calcd for C15H21NO3 294.16998, found
294.16957.
■
sı
N-Phenyl-2,4,6-trimethoxybenzamide (5b-Ph). This compound
was prepared using the microwave method: yield 92 mg (64%) as a
white solid. Column chromatography (silica gel, ethyl acetate/
petroleum ether 1/3). 1H NMR (400 MHz, chloroform-d): δ 7.64 (d,
J = 7.9 Hz, 2H), 7.52 (s, 1H), 7.33 (t, J = 7.8 Hz, 2H), 7.10 (t, J = 7.4
Hz, 1H), 6.14 (s, 2H), 3.84 (s, 3H), 3.82 (s, 6H). 13C{1H} NMR
(100 MHz, chloroform-d): δ 163.54, 162.44, 158.85, 138.54, 128.90,
123.92, 119.55, 109.01, 90.76, 56.03, 55.45. HR-ESMS (ESI): m/z
[M + H]+ calcd for C15H21NO3 288.12303, found 288.12296.
N-(4-(Trifluoromethyl)phenyl)-2,4,6-trimethoxybenzamide (5b-
CF3Ph). This compound was prepared using the microwave method:
yield 106 mg (60%) as a white solid; Column chromatography (silica
gel, ethyl acetate/petroleum ether = 1:3); 1H NMR (400 MHz,
Tables of DFT calculated thermochemistry for trans-
formation of aromatic carboxylic acids into amidines,
mass spectra showing decarboxylation and fragmenta-
tion reactions of adducts of organopalladium cations and
1
isocyanates, H and 13C{1H} NMR and HRMS spectra
of all isolated benzamides, discussion of crystallographic
studies, tables for crystal data and structure refinement
(PDF)
Cartesian coordinates for the calculated structures
(XYZ)
L
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Accession Codes
CCDC 1937864−1937866 and 1966555−1966557 contain
the supplementary crystallographic data for this paper. These
data can be obtained free of charge via www.ccdc.cam.ac.uk/
data_request/cif, or by emailing data_request@ccdc.cam.ac.
uk, or by contacting The Cambridge Crystallographic Data
Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44
1223 336033.
AUTHOR INFORMATION
■
Corresponding Author
Richard A. J. O’Hair − School of Chemistry, Bio21 Institute of
Molecular Science and Biotechnology, The University of
Melbourne, Parkville 3010, Australia; orcid.org/0000-
0002-8044-0502; Phone: +613 8344-2452; Email: rohair@
unimelb.edu.au; Fax: +613 9347-5180
Authors
Yang Yang − School of Chemistry, Bio21 Institute of Molecular
Science and Biotechnology, The University of Melbourne,
Parkville 3010, Australia
Allan J. Canty − School of Natural Sciences-Chemistry,
University of Tasmania, Hobart 7001, Australia; orcid.org/
0000-0003-4091-6040
Alasdair I. McKay − School of Chemistry, Bio21 Institute of
Molecular Science and Biotechnology, The University of
Melbourne, Parkville 3010, Australia
Paul S. Donnelly − School of Chemistry, Bio21 Institute of
Molecular Science and Biotechnology, The University of
Melbourne, Parkville 3010, Australia; orcid.org/0000-
0001-5373-0080
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.organomet.9b00820
(15) There is a surprising lack of known heats of formation of
aromatic amides. Using the following gas-phase heats of formation, eq
1 is predicted to be exothermic by 22.7 kcal/mol for the
transformation of benzoic acid to benzamide: ΔfH(PhCO2H) =
−70.3 kcal/mol; ΔfH(HNCO) = −25 kcal/mol; ΔfH(PhC(O)NH2)
= −24 kcal/mol; ΔfH(CO2) = −94 kcal/mol. Data are from: Lias, S.
G.; Bartmess, J. E.; Liebman, J. F.; Holmes, J. L.; Levin, R. D.;
Mallard, W. G., Gas-Phase Ion and Neutral Thermochemistry, J. Phys.
Chem. Ref. Data 1988, 17, Supplement 1.
(16) Rodriguez, N.; Goossen, L. J. Decarboxylative coupling
reactions: a modern strategy for C-C-bond formation. Chem. Soc.
Rev. 2011, 40, 5030−5048.
(17) Goossen, L. J.; Rodriguez, N.; Goossen, K. Carboxylic acids as
substrates in homogeneous catalysis. Angew. Chem., Int. Ed. 2008, 47,
3100−3120.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We acknowledge the support of the ARC (DP180101187
funding to A.J.C., P.S.D., and R.A.J.O.), and the National
Computing Infrastructure. The Thermo Orbitrap Fusion
Lumos mass spectrometer was accessed via the Bio21 Mass
Spectrometry and Proteomics Facility with thanks. The single-
crystal X-ray diffractometers used in this study were funded by
the ARC (LE170100065).
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