Palladium-Catalyzed Isomerization/(Cyclo)carbonylation of Pentenamides: a Mechanistic Study of the Chemo- and Regioselectivity

Article abstract of DOI:10.1002/cctc.201700345

A new isomerizing ring-closing amidocarbonylation reaction is reported using Pd catalysis with bulky diphosphane ligands. From terminal as well as internal pentenamide isomers (PAs), cyclic imides were obtained in good yield (92 %) with cationic Pd catalysts supported by bis-PCg ligands (PCg=6-phospha-2,4,8-trioxa-1,3,5,7-tetramethyladamant-6-yl). An excess of strong acid is required to obtain high selectivity for imide products. From a low-temperature NMR study it was deduced that N coordination of the amide moiety is responsible for a high selectivity to cyclic imide products. In weakly acidic conditions, O coordination of the amide functionality leads to the formation of cyanoacids (i.e., 5-cyanovaleric acid, 2-methyl-4-cyanobutyric acid and 2-ethyl-3-cyanopropionic acid). It is proposed that the formation of these cyanoacids occurs through a novel intramolecular tandem dehydrating hydroxycarbonylation reaction of PAs. This reaction also occurs in intermolecular versions of amidocarbonylation with mixtures of alkene and amide substrates. Experiments with N-alkylated amides have been instrumental in developing mechanistic models. The strong acid co-catalyst ensures double-bond isomerization to occur faster than product formation, resulting in the same product mixture, irrespective of the use of terminal or internal pentenamides. The remaining challenge is to arrive at the desired adipimide by overcoming the undesirable regioselectivity caused by chelation of the amide.

Full text of DOI:10.1002/cctc.201700345

Accepted Article
Title: Palladium-Catalyzed Isomerization/(Cyclo)carbonylation
of Pentenamides: a Mechanistic Study of the Chemo- and
Regioselectivity
Authors: Bart Limburg, Yann Gloaguen, Hans M. de Bruijn, Eite Drent,
and Elisabeth Bouwman
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10.1002/cctc.201700345
ChemCatChem
Palladium-Catalyzed Isomerization/(Cyclo)carbonylation of Pentenamides:
a Mechanistic Study of the Chemo- and Regioselectivity
Bart Limburg,‡ Yann Gloaguen,‡ Hans M. de Bruijn, Eite Drent, and Elisabeth Bouwman*
Leiden Institute of Chemistry, Gorlaeus Laboratories, Leiden University, P.O. Box 9502, 2300 RA Leiden (The Netherlands)
‡ Equal contributions
* Corresponding author; bouwman@chem.leidenuniv.nl
Abstract: A new isomerizing ring-closing amidocarbonylation reaction is reported using Pd-catalysis with bulky
diphosphane ligands. From terminal as well as internal pentenamide isomers (PAs), cyclic imides were obtained
in good yield (92%) with cationic Pd catalysts supported by bis-PCg ligands (PCg = 6-phospha-2,4,8 trioxa-
1,3,5,7-tetramethyladamant-6-yl). An excess of strong acid is required to obtain high selectivity for imide
products. From a low-temperature NMR study it was deduced that N-coordination of the amide moiety is
responsible for a high selectivity to cyclic imide products. In weakly acidic conditions O-coordination of the
amide functionality leads to the formation of cyanoacids (i.e., 5-cyanovaleric acid, 2-methyl-4-cyanobutyric acid
and 2-ethyl-3-cyanopropionic acid). It is proposed that the formation of these cyanoacids occurs through a
novel intramolecular tandem de-hydrating hydroxycarbonylation reaction of PA’s. This reaction also occurs in
intermolecular versions of amidocarbonylation with mixtures of alkene and amide substrates. Experiments with
N-alkylated amides have been instrumental in developing mechanistic models. The strong acid co-catalyst
ensures double-bond isomerization to occur faster than product formation, resulting in the same product
mixture, irrespective of the use of terminal or internal pentenamides. The remaining challenge is to arrive at the
desired adipimide by overcoming the undesirable regioselectivity caused by chelation of the amide.
Keywords: caprolactam • biomass • palladium-diphosphane • tandem isomerization/amido-carbonylation • imide •
cyanoacid
Introduction
Developing alternative routes to bulk and fine chemicals based on renewable biomass is a highly desirable goal
of chemical industry. Lignocellulosic biomass is the most abundantly available raw material on earth and has
attracted a lot of interest as sustainable feedstock.[1-2] Its potential conversion into various platform chemicals
such as 5-hydroxymethylfurfural,[3] furfural, levulinic acid,[4] and γ-valerolactone (GVL)[5] is expected to pave the
way for economical and sustainable production of various bulk chemicals and liquid fuels. For these compounds
a sufficient volume of operation can be achieved to significantly impact the chemical industry’s ambitions to
reduce greenhouse gas emissions. ε-Caprolactam (CAP) is an example of a potentially accessible bulk chemical
from biomass; CAP serves as the precursor for nylon-6, an extensively produced polymer (about 4 Mt/year).
CAP’s traditional synthesis from oil-based feedstock involves high energy consumption and substantial salt co-
production.[6-7]
We have shown that bio-based GVL can be converted into a mixture of isomeric pentenamides (PAs), which
ultimately yields ε-caprolactam via a Rh-catalyzed tandem isomerizing intramolecular hydroamidomethylation
reaction i.e. isomerization, hydroformylation, cyclization and subsequent hydrogenation (Scheme 1, right).[8-9]
The major limitation for the viability of this overall process, in terms of both activity and selectivity, is the rather
poor performance of the Rh/Xantphos catalyst for the selective transformation of the internal olefins 2-PA and
3-PA, the latter being the major isomer obtained from GVL. The rate of isomerization was shown to be lower
than the rate of hydrogenation, resulting in substantial pentanamide (valeramide) production and thus severe
1
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10.1002/cctc.201700345
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feedstock loss. For a realistic process based on GVL and using this Rh-catalyst, an energy-intensive pre-
isomerization/separation step of the mixture of PAs would be required.
Scheme 1. Previously reported (Rh-cat, right)[8-9] and envisioned catalytic route (Pd-cat, left) for the conversion of
(biomass-derived) pentenamides to caprolactam.
In recent years, palladium catalysts have found widespread use in alkene carbonylation reactions such as
hydroxy/alkoxy- as well as amino-[10-15] and amido-carbonylation processes.[16] Importantly, Pd(II) catalysts
bearing electron-rich, bulky diphosphane ligands (typically bis(di-tert-butylphosphanyl)xylene, L1), have been
shown to efficiently promote the selective isomerizing hydroxy/methoxy carbonylation of internal alkenes
endowed with a functional group (acid or ester) to linear di-acids/esters.[17-19] The high regioselectivity for linear
carbonylation products with these catalysts can be seen as a consequence of the almost exclusive carbonylation
at the terminal C-atom of a paraffinic chain. This unique attribute can, in turn, be ascribed to two underlying
catalytic phenomena: (i) rapid ‘running’ of Pd-H species, under a CO atmosphere, along the carbon chain
followed by (ii) an overall rate-determining termination reaction (forming e.g. acid or ester product) from the
Pd-acyl species with regeneration of the starting Pd-H species. The latter occurs via attack of the nucleophilic
reagent (alcohol/water) at the Pd-acyl center, which is mainly governed by steric factors induced by the
supporting bulky ligand. As a consequence, termination will proceed much faster at the least sterically hindered
terminal C-atom, thus producing a linear carboxylic acid or ester with high selectivity.
Inspired by this chemistry, we took up the challenge to develop an intramolecular isomerizing carbonylation
reaction, applied to the substrate PA and aiming to form selectively adipimide 7-i (Scheme 1, left).[20-21] We thus
envisioned another route to (bio-based) CAP that separates the isomerizing carbonylation of PA from reduction
by H2. In this way, loss of PA by hydrogenation will be prevented, whereas the same high overall theoretical
atom-efficiency in CAP production from PA can be achieved.[22-23] Semi-hydrogenation of lactams has indeed
been reported previously.[22] Herein, we present the results of our investigations into the intramolecular
amidocarbonylation of pentenamides.
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Results
Pd-catalyzed amidocarbonylation of pentenamides
Initially, the PdII/L1/methane sulfonic acid (HOMs) catalyst system reported by Low et al.[19] was applied to the
substrate 4-pentenamide (4-PA). A disappointingly low yield of cyclic imide carbonylation products (5-i/6-i) was
obtained (Table 1, entry 1). Both an in situ mixture of Pd(OAc)2/L1/HOMs or a mixture of the preformed
complex [Pd(L1)(dba)] and HOMs were used as catalyst precursors; both procedures gave essentially the same
results (Table 1, entry 1 vs. entry 2). The yield of any of the possible cyclo-amidocarbonylation products that can
be produced in this carbonylation reaction appears to be rather low using ligand L1; in particular the desired
seven-membered cyclic imide product 7-i corresponding to cyclo-carbonylation at the terminal carbon atom
was not observed.
After surveying a series of parameters (type of ligand, type of Pd source, type of acid, type of solvent and CO
pressure, Tables S2-6) in the carbonylation of PA isomers, we identified catalytic systems and conditions for
formation of intramolecular carbonylation products 5-i and 6-i in good yields. The bulky “cage ligands” L2 and
L3 (PCg = 6-phospha-2,4,8-trioxa-1,3,5,7-tetramethyladamant-6-yl) proved to be much more suitable for
facilitating the carbonylation reaction of the amide substrate (Table 1, entries 3-8). The catalysts supported by
Table 1. Pd-catalyzed cyclo-amidocarbonylation of PA: Screening of ligands.[a]
/ HOMs
[cat]
CO
H
N
H
N
O
O
O
O
NH2
+
O
PA
5-i
6-i
=
L
[cat]
( )Pd(dba)
tBu2
tBu2
P
Cg
P
O
Cg
P
O
P
=
PCg
P
P
Cg
P
P
tBu2
P
O
Cg
Cg
L1
L4
L2
L3
Entry
Ligand
L1
Substrate
4-PA
Imides (%) [b]
5-i:6-i [b]
33:67
31:69
78:22
79:21
80:20
94:6
1
2[c]
3
5
L1
4-PA
9
L2
4-PA
64
66
63
92
85
88
12
4
L2
3-PA
5
L2
2-PA
6
L3
4-PA
7
L3
3-PA
94:6
8
L3
2-PA
94:6
9
L4
4-PA
81:19
[a] Reaction conditions: 1 mmol of PA, 0.5 mol% [(L)Pd(dba)] (preformed), 15 mol%
HOMs, V(diglyme) =2 .5 mL, undecane (internal standard, 0.250 mL), 100 °C, 16 h, PCO
=
50 bar. [b] Determined by GC using undecane as an internal standard. The yield of imides
was in agreement with the conversion. [c] Same as [a] with catalyst prepared in situ from
predissolved mixture of Pd(OAc)2 and L (1:1.2) to which 15 mol% HOMs (vs. PA) is added.
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ligands L2-L4 in combination with HOMs (30 eq/Pd) as co-catalyst, showed the exclusive formation of cyclic
imide products 5-i and 6-i. Remarkably, with both ligands L2 and L3 the yields and ratio of isomeric products
obtained are independent of the starting PA isomer as substrate. The regioselectivity to 6-i appeared
significantly higher for catalysts supported by L2 (Table 1, entries 3-5).
Attempts to influence the regioselectivity results in different chemoselectivity
We aimed to explore which parameters could influence the regioselectivity and examined a variety of
conditions. The carbonylation reaction with 4-PA as substrate was conducted as a model reaction using L2 as
ligand. As we anticipated that the interaction of the pendent amide functionality of the pentenamide substrate
is important in the formation of the ring-closed product, we hoped to identify additives which could either
interact with the Pd-bound pendent amide functionality or mimic its ability to reversibly coordinate to Pd and
consequently influence the catalysts’ regioselectivity. We focused on investigating the use of
N-methylpyrrolidone (NMP) as a compound that could likely compete with the coordination of the amide group
and promote the isomerization to proceed to the terminal position. Surprisingly, instead of forming 7-i, the
presence of NMP led to the formation of isomeric cyanoacids (CAs) 2-methyl-4-cyanobutyric acid (MCA) and
2-ethyl-3-cyanopropionic acid (ECA) (Table 2).[24]
Among a group of related additives {dimethylformamide (DMF), dimethylacetamide (DMA), diethylacetamide
(DEA), N-methylthiopyrrolidone (thio-NMP)}, NMP turned out to be the most effective to promote cyanoacid
formation at 100 °C (Table S7). Further experiments showed the use of lower temperatures to also favor
cyanoacid formation. These experiments were done at higher PA concentration to compensate for the decrease
in conversion caused by the presence of the promoter and the lower reaction temperature (Tables S8-9). In the
absence of promoter, but at a reaction temperature of 60 °C the increase in substrate concentration already
leads to the formation of the two cyanoacids ECA and MCA (5%, Table 2, entry 1 and 2). This shows that the
substrate amide functionality of PAs themselves to a certain extent can exert a similar effect as the addition of
an external N-alkylated amide. The addition of NMP has the most prominent effect when combined with the
catalytic system using L2 (64% selectivity to CAs vs. 36% of imides when starting from 4-PA, entry 3), however at
low conversions (11-17%). The use of L3 gives better yields of cyclo-carbonylation products (60%) and lower
cyanoacid selectivity (30% CAs vs. 70% imides, entry 8). Similar to the experiments without NMP in Table 1, we
also observed that in presence of NMP and even at the lower reaction temperature of 60 °C the catalytic
regioselectivity was largely independent from the starting PA isomer substrate, both with L2 (Table 2, entries 3
and 4) and with L3 (Table 2, entries 8 and 9). Only with DMA added, it seemed that the catalyst regioselectivity
became somewhat more dependent on the starting PA isomer (Table 2, entries 5 and 6). The separation of ECA
and MCA on GC furthermore showed that similarly to the cycloimide products 5-i and 6-i, the isomeric ratio
ECA:MCA increases when using L3 (93% ECA with L3 vs.62% with L2, from 4-PA, see Table S9).
Using the catalyst and co-catalyst at half the concentration results in very similar selectivities (Table 2, entry 10
vs. entry 8). Applying a lower CO pressure of 5 bar instead of the common CO pressure of 50 bar (Table 2, entry
11) gives a significantly higher yield of 5-i, but with a remarkable reduction in yield of CAs. A higher reaction
temperature (120 °C, Table 2, entry 12, cf. entry 3 at 60 °C) also leads to increased yield of imides 5-i/6-i, with
no observable formation of CAs.
Finally, exclusively imides were formed when using N-methyl-2-pentenamide as the substrate, predominantly
the N-methyl-2-ethylsuccinimide isomer (Tabel 2, entry 13). During the course of our study, Beller et al.
reported Pd-catalyzed intermolecular amidocarbonylation reactions, using however exclusively N-alkylated
secondary amides and terminal alkenes as substrates under essentially acid-free conditions.[16] We also applied
the amidocarbonylation conditions of this report using PdI2 as Pd source and oxydi-2,1-phenylene
bis(diphenylphosphane) (DPEPhos) as ligand for our substrates 2-, 3-, or 4-PA, thus containing a primary amide
functionality. The ring-closing carbonylation reaction only occurred when employing 4-PA, the substrate with a
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Table 2. Amidocarbonylation of pentenamides: the formation of cyanoacids MCA and
ECA vs. imides.[a]
Entry
1[c]
2[c]
3
Ligand
Substrate
4-PA
Promoter Yield (%)[b]
5-i:6-i:CAs[b]
65:30:5
66:29:5
17:19:64
26:34:40
22:24:54
35:30:35
86:14:0
62:8:30
61:7:32
61:9:30
87:5:8
L2
L2
L2
L2
L2
L2
L3
L3
L3
L3
L3
L2
L3
-
51
48
3-PA
-
4-PA
NMP
NMP
DMA
DMA
-
17
4
3-PA
11
5
4-PA
10
6
3-PA
14
7
4-PA
52
8
4-PA
NMP
NMP
NMP
NMP
NMP
NMP
61
9
3-PA
49
10[d]
11[e]
12[f]
13[g]
4-PA
53
4-PA
84
4-PA
79
78:22:0
86:14[i]
N-Methyl-2-PA
N.D.[h]
[a] 2 mmol of PA, 1 mol% (L)Pd(dba), 30 mol% HOMs, V(promoter) = 1 mL (5 eq vs PA),
undecane (IS: 0.250 mL), 60 °C, 16 h, PCO = 50b. [b] Yield and selectivity in carbonylation
products (imides + cyanoacids) were determined by GC using undecane internal
standard. The sum of the yields of imides and CAs was in agreement with the
conversion; CAs (cyanoacids) = MCA + ECA. [c] No promoter, V(diglyme) = 1 mL. [d]
Same as [a] but with 0.5 mol% [(L)Pd(dba)], 15 mol% HOMs. [e] same as [a] but PCO =5
bar. [f] Same as [a] but with 0.25 mol% [(L)Pd(dba)], 7.5 mol% HOMs,
V(diglyme+promoter {5 eq. vs PA}) = 2.5 mL, undecane (IS):0.250 mL, 120 ˚C, 16 h,
PCO=50 bar. [g] 2 mmol N-methyl-2-PA, 1 mol% Pd(OAc)2, 1.2 mol% L3, 10 mol% HOMs,
V(NMP)= 1 mL, 60 ˚C, 16 hr. Yield was not determined. [h] N.D. : exact yield not
determined. [i] The products from this reaction are 5-membered ring N-methyl-2-
ethylsuccinimide and 6-membered ring N-methyl-2-methylglutarimide.
terminal alkene. We did not obtain any conversion using 3-PA or 2-PA as substrate, in agreement with the work
of Beller, who reported that internal alkenes are totally unreactive under these conditions. The reaction using
the Beller conditions with 4-PA as substrate yielded 6-i and the desired 7-i in very low yields (1.5% and 1.2%,
respectively). Surprisingly, also the isomeric cyanoacids MCA and 5-cyanovaleric acid (CVA), and some
compounds with higher GC retention time were formed, presumably intermolecular reaction products (dimers
and oligomers; see Figure S1). The acid-free protocol reported by Beller et al.[16] thus appeared to be unsuitable
for the synthesis of 7-i from internal pentenamides.
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NMR study
It was surmised that the coordination mode of the primary amide functionality of the substrate at a cationic
[Pd-acyl]+ species might play a role in determining the chemoselectivity of amidocarbonylation. Therefore we
undertook an NMR study to elucidate the possible effects of the strong acid co-catalyst and the basic selectivity
modifier NMP on the coordination mode of amides to a PdII centre. To this end, [Pd(MeCN)4](BF4)2 and 1.05 eq
of ligand L3 were dissolved in deuterated acetone; to this solution acetamide was added, serving as a mimic for
the amide functionality. Because ligand-exchange reactions at the PdII ion occur at the NMR timescale, very
1
broad signals were observed on H NMR for the NH2 protons of acetamide at room temperature. The solution
was cooled down to –65 °C in order to slow down the ligand-exchange kinetics (see Figure S2). A rather complex
spectrum was obtained due to different coordination modes and the inequivalence of the two NH2 protons. To
differentiate the tautomeric forms of the amide (two protons on the N) from the iminol (one proton on the N,
one proton on the O), 15N-labeled acetamide was used. Every proton attached directly to the 15N of acetamide is
split into two peaks with a large 1JH-N (~90 Hz) coupling, and therefore 15N-decoupled proton NMR spectra were
recorded to simplify the spectra (Figure 1, bottom trace). By means of a 1H–15N HSQC measurement (Figure S3),
three differently coordinated acetamide species were identified, all having two inequivalent protons bound to
15
the nitrogen atom. The N chemical shifts were found at 124.4, 126.3 and 130.4 ppm tentatively assigned to
species A, B and C (Figure 1). We did not observe the iminol tautomer, that was previously shown to be the
favored coordination mode for acetamide to a [(diethylenetriamine)PtII]2+ centre.[25] For two of the observed
species (A and B), the N–H peaks in 1H NMR were in rapid exchange with free acetamide (indicated with *), as
observed by positive cross-peaks in NOESY (Figure S7). The remaining species C was not exchanging rapidly with
free acetamide, indicating that compound C is kinetically more stable. It has been reported that the kinetic
product of amide coordination to PtII is bound with the O atom, and that the thermodynamically more stable N-
coordination requires heating or a longer period of reaction time.[25-27] Therefore, in analogy, we tentatively
assign species A and B as two isomers coordinated to PdII with the O of acetamide, and species C as an N-
coordinated isomer (see Scheme 2).[25-27]
1
Figure 1. H{15N} NMR spectra of a solution of [Pd(MeCN)4](BF4)2 (20 µmol), L3 (21 µmol) and 15N-acetamide (68 µmol) in
acetone-d6 (0.6 mL). The NH2 protons of different coordinated acetamide species (A, B, C and D), as well as free acetamide
(*) are indicated. The spectra with added HOMs (0.7 eq to Pd), and HOMs + NMP (0.5 eq to Pd, and 1.5 eq to Pd in total)
are also shown.
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Scheme 2. Proposed coordination modes of acetamide to [Pd(L3)(L)]2+ (L = MeCN, acetone, or NMP).
Upon the addition of HOMs (2 µL, 0.7 eq to Pd), species A and B disappear, indicating dissociation of the amide
15
(the peaks collapsed into two broad signals, connected to a single N at 125.8 ppm of free acetamide, *), as
shown in Figure 1. The peaks of species C shifted but remained. The only mode of coordination for acetamide
observed in the presence of HOMs thus is the N-coordinated species C. The reason that upon addition of acid
the amide dissociates from species A and B can be understood as a competition between the binding of a soft
Lewis-acid palladium ion or the hard Lewis-acid proton to the hard Lewis-base O atom. In contrast, N-
protonation is highly unfavored,[28] therefore such competition is absent for species C.
Upon addition of NMP the strength of the acid is reduced by almost an order of magnitude (pKa of HOMs = –1.9,
while pKa of protonated N-methylacetamide = –1),[28] leading to an upfield shift of the free acetamide peaks (*)
and appearance of another type of coordinated acetamide (species D). At 0.5 equivalent of NMP a broad peak is
observed in proton NMR that splits into two peaks upon addition of more NMP (30 µL, 1.5 eq to Pd in total). The
15
chemical shift of the N of this species is at 126.7 ppm, which corresponds roughly to that for species B in the
absence of HOMs or added NMP, and we therefore conclude a similar coordination mode to be present in
species D (Figures S2-4). The observation of a single broad peak in the presence of a small amount of NMP
might be due to fast proton exchange at the amide N atom, leading to an averaged signal. We assigned
coordination mode B as an O-coordinated acetamide species; it thus seems reasonable to conclude that the
presence of a large amount of the weak base NMP leads to the reappearance of an O-coordinated amide PdII
species.
Intermolecular amidocarbonylation
To connect our studies with the intermolecular amidocarbonylation of 1-octene with N-methylacetamide under
acid-free conditions recently reported by Beller et al.,[16] we repeated one of the reported experiments (i.e., 2
mmol 1-octene, 2 mmol N-methylacetamide, 0.5 mol% PdI2, 1 mol% DPEPhos, 2 mL diglyme, T = 105 °C, PCO = 50
bar). As reported, the corresponding N-methylimide was produced (Table 3, entry 1).
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Table 3. Chemoselectivity towards imide or carboxylic acid/nitrile formation for different substrates
and conditions in the intermolecular amidocarbonylation reaction.
entry
1
substrates
conditions
Main product
1-octene
N-methyl acetamide
[a]
N-methyl-N-acetylnonanamide
1-octene
acetamide
nonanoic acid
acetonitrile[d]
2
3
4
5
[a]
[a]
[b]
[c]
1-octene
pentanamide
nonanoic acid
pentanenitrile
1-octene
pentanamide
N-pentanoylnonanamide
1-octene
pentanamide
nonanoic acid
pentanenitrile
[a] 2 mmol 1-octene, 2 mmol amide, 0.5 mol% PdI2, 1 mol% DPEPhos, V(diglyme) = 2 mL, 105 °C, 20
h, PCO = 50 bar. [b] 2 mmol 1-octene, 2 mmol pentanamide, 1 mol% Pd(OAc)2, 1.2 mol% L3, 10 mol%
HOMs, V(diglyme) = 2 mL, 105 °C, 16 h. [c] 2 mmol 1-octene, 2 mmol pentanamide, 1 mol%
Pd(OAc)2, 1.2 mol% L3, 10 mol% HOMs, V(NMP) = 1 mL, 60 °C, 16 h. [d] acetonitrile could not be
observed quantitatively due to its low boiling point, overlapping with impurities on GC and its low
response factor.
However, when non-alkylated acetamide was used instead, the almost exclusively observed products were
nonanoic acid and a small quantity of 2-methyloctanoic acid, along with acetonitrile (Table 3, entry 2). When
pentanamide was used instead of acetamide, pentanenitrile was quantitatively observed as product besides the
carboxylic acids in a 1:1 ratio. In contrast, in the acidic conditions described in this work (Table 3, entry 4), the
reaction between 1-octene and pentanamide indeed yielded the imide product alongside small amounts of
nonanoic acid and 2-methyloctanoic acid. Furthermore, when the reaction was performed in the presence of
acid, but in NMP at 60 °C (Table 3, entry 5), again only nonanoic acid, 2-methyloctanoic acid and pentanenitrile
were formed, similarly to the intramolecular formation of cyanoacids ECA and MCA when PA is used as the
substrate.
Discussion
Catalysis of isomerizing cyclo-amidocarbonylation of PA
Above we present a new Pd-catalyzed carbonylative transformation of pentenamides – termed isomerizing
cyclo-amidocarbonylation – to afford cyclic imides in high yields. The transformation is composed of a tandem
sequence of reactions, i.e., alkene bond isomerization and intramolecular amidocarbonylation. Although the
exact mechanism of the reactions must be subject of further study, our catalytic results suggest that the
reaction proceeds via a similar mechanistic pathway as the well-studied isomerizing alkoxy- or
hydroxycarbonylation of alkenes with [LPd-H]+ as the actual active catalyst species.[17-19, 29-30]
The first Pd-H species can generally be formed in situ from a variety of palladium sources. In our reaction, the
active PdII-H catalyst is generated in situ by reacting a strong acid (e.g. HOMs) with either a preformed LPd0
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complex or with a 1:1 mixture of a PdII salt with a ligand L, in the presence of CO and PA as substrate. The use of
a preformed LPd0 precursor proved to be a most convenient and reproducible protocol for the formation of an
active catalytic system (Tables 1, 2). This is in line with the general observation that [L1Pd0(dba)] in combination
with a strong acid serves as a suitable catalyst precursor mixture, by protonation of the Pd0 center generating
the cationic species [L1PdII–H]+(OMs)− active in e.g. alkene methoxycarbonylation.[31] Starting from a 1:1 mixture
of a PdII salt and a ligand L with excess of HOMs essentially the same catalyst complex is formed in situ. Catalyst
formation supposedly proceeds under reaction conditions via stoichiometric carbonylative reduction of LPdII by
the alkene and a nucleophilic reagent, such as water, alcohol (or in our case the amide).[30, 32] We have indeed
experimentally verified that both protocols gave similar catalytic results (see Table 1, entries 1 and 2).
The species [LPdII–H]+(OMs)− can start the catalytic cycle for the reaction by migration of the hydride to a
coordinated alkene; subsequent β-hydrogen elimination, migration and CO insertion generates a mixture of
several [LPd-alkyl]+ and [LPd-acyl]+ species. It is thought that the final imide product-forming step involves a
nucleophilic attack of the amide at the Pd-acyl species resulting in amidocarbonylation in analogy to the
reaction with alcohols in alkoxycarbonylation or with water in hydroxycarbonylation.[19] Although the detailed
mechanism of this final step is not known, it is thought that the nucleophilic attack of the amide, in analogy with
those of alcohols and water,[33-34] involves N-coordination of the amide at the [LPdII-acyl]+ center followed by
deprotonation of the coordinated amide, upon which the product imide is generated by reductive elimination.
This reaction sequence thus formally generates an [LPd0] species and one equivalent of H+, which together
subsequently or concertedly regenerates [LPdII–H]+(OMs)−.
Reported mechanistic studies on related intermolecular isomerizing methoxycarbonylation reactions of alkenes
catalyzed by cationic [LPd–H]+ complexes indicate relatively low barriers and therefore apparent reversibility of
both migration/β-elimination of the hydride as well as subsequent CO (de-) insertion steps in the Pd-alkyl
species under the prevailing reaction conditions.[31] The excess of a strong acid in our catalytic experiments
fulfills a co-catalytic role, circumventing the buildup of Pd0 species through rapid protonation of any [LPd0]
species formed, thus avoiding regeneration of the actual active catalyst [LPdII–H]+(OMs)− to become rate
determining (see Scheme 3). Furthermore, the excess of strong acid co-catalyst leads to rapid alkene bond
isomerization by maintaining a relatively high concentration of [LPdII–H]+. The general catalytic cycle proposed
for isomerizing amidocarbonylation rationalizes the formation of cyclic imides such as 5-i, 6-i from PA as
substrate (Scheme 3, two left reaction pathways).
Regioselectivity in isomerizing cyclo-amidocarbonylation of PA
Formation of 5-i was always favored when a catalytic system comprising one of the ‘cage’ ligands L2, L3 or L4
was used, with a 5-i:6-i regioselectivity of respectively ~80:20, 94:6 and 81:19 (Table 1, entries 3, 6 and 9).
Furthermore, it appeared that for catalysts supported by each of these ligands, not only the regioselectivity, but
also the catalytic activity is independent of the double bond position in the starting PA isomer (Table 1, entries
3–5 for L2, and 6–8 for L3). These results thus show that one of the requirements for a selective isomerizing
carbonylation reaction is fulfilled: alkene bond isomerization is much faster than the overall product formation
rate. Moreover, the reaction selectively yielded imides only; no other products were observed. However,
carbonylation and product formation clearly does not occur at the least hindered terminal C-atom (Scheme 3,
right pathway to 7-i).
Based on the general mechanistic work on related intermolecular isomerizing carbonylation reactions,[29-30] we
can propose a likely rationalization of the observed regioselectivity. Although the catalyst has a high alkene
bond isomerization activity, as deduced from the independence of the results on the used PA isomer, still only
the 5- and 6-membered cyclic imides are produced. This outcome likely stems from the relative stabilities of an
equilibrated mixture of the 5-, 6-membered and 7-membered palladacyclic species (comprising both the [LPd-
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alkyl]+ and [LPd-acyl]+ intermediates, Scheme 3) in combination with the rate of intramolecular nucleophilic
attack of the amide at the respective Pd-acyl species.
Scheme 3. Chelation control of the regioselectivity outcome in LPd-catalyzed PA cyclo-amidocarbonylation reaction. For
clarity, weakly coordinated OMs– anions associated with catalytic [LPd]+ centre not shown. The chelation of the amide in
the rightmost pathway is depicted as absent to illustrate why 7-i is not formed.
One important kinetic factor of cyclic imide formation must be the local concentration of the pendent amide
moiety in the neighborhood of the Pd center, which is determined by its chelation strength. We thus
hypothetically identify chelation of the amide moiety as the main obstacle for amidocarbonylation at the least
hindered terminal C-atom of PA, since this would involve significantly less abundantly present 7-membered ring
(Pd-alkyl) and 8-membered ring (Pd-acyl) intermediates in which chelation is weak (depicted as absent in
Scheme 3, right pathway). In contrast to the strongly favored route towards 5-i involving a relatively stable 6-
membered ring Pd-acyl, the one yielding 6-i involves a less abundantly present 7-membered ring Pd-acyl
complex. Comparing the results of the use of two similar cage ligands L2 and L3, it is clear that L2 brings about
more steric congestion at the coordination sites opposite the phosphorus donors due to a larger bite-angle of
the longer C4 spacer, which destabilizes chelation and results in lower overall rates of total imide (5-i+6-i)
formation as is apparent from Table 1 (entries 2–4 for L2 and 5–7 for L3). At the same time, the higher steric
congestion induced by L2 destabilizes the ethyl-substituted Pd-alkyl complex, instead driving the complex to
form more of the methyl-substituted Pd-alkyl intermediate rationalizing the lower 5-i:6-i ratio for L2 relative to
L3. A plausible explanation for the poor performance of L1 in our case would then be that its induced steric
congestion by the bulkier -P(tBu)2 moieties at the Pd center is such that it prevents chelation to take place,
thereby hampering the ring-closing termination reaction. However, electronic factors operating both in
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chelation of the [LPd-acyl]+ species and the resulting nucleophilicity of the amide cannot be excluded either, as
the cage ligands L2 and L3 bear electron-withdrawing tris-oxa-adamantyl substituents vs. the electron-donating
tert-butyl substituents in L1. The electron-withdrawing ligands could favor coordination of the amide and
thereby the succeptibility of the [LPd-acyl]+ intermediate for nucleophilic attack by rendering the Pd center
more electrophilic.
Chemoselectivity in (cyclo)amidocarbonylation
Our NMR study indicates that both N- and O-coordinated amide PdII species are present in an LPd(II)/acetamide
mixture in neutral conditions. The change in chemoselectivity of LPdII/H+ catalyzed amidocarbonylation of PA
from imides to cyanoacids with addition of NMP correlates well with our NMR study indicating exclusive
N-coordination of amide to a LPdII species to persist under acidic conditions. Upon addition of the weakly basic
NMP, and thus when acidity is quenched, the NMR signals belonging to compound ‘D’ indicate re-appearance of
an O-coordinated PdII amide species. We thus explain the observed different chemoselectivity of
amidocarbonylation in absence or presence of acid with the mechanism depicted in Scheme 4. The amide
–
coordination behavior studied with a cationic LPdX2 (X = BF4 ) species can be related to coordination of the
pendent amide moiety of PA in catalytically relevant cationic [LPd-acyl]+(OMs–) species. In view of the similarity
in cationic nature of both Pd centers, we consider such an extrapolation to be a reasonable assumption. Thus as
shown in Scheme 4, N-coordination of the amide moiety (PdN) to an LPdII–acyl species leads to the formation of
imides via nucleophilic attack of this intermediate (reaction c), whereas O-coordination existing under acid-
quenching conditions (PdO) could hypothetically lead to isoimides via nuclophilic attack of the carbonyl O atom
(reaction d). The cyanoacid could be formed by a subsequent rearrangement of the isoimide via reaction e.
Isoimides are indeed quite unstable molecules;[35-36] they have been suggested to be intermediates in the
formation of the thermodynamically favored imides (reaction f).[35-36]
As isoimides were not observed in any product mixture an immediate in situ rearrangement to isomeric imides
and/or cyanocarboxylic acid should thus be considered. DFT energy calculations on the three isomeric
compounds 2-ethyl-succinimide (5-i), 2-ethyl-succinisoimide (5-ii) and ECA showed that the isoimide (5-ii) is
thermodynamically the most unstable compound of the three. The ΔG values (gas phase) of 5-ii and ECA
relative to 5-i are +16.9 and +14.2 kcal·mol–1 (Figure 2). The same trend was found for the regioisomers 6-i, 6-ii,
and MCA, as well as for 7-i, 7-ii, and CVA; the isoimides 6-ii and 7-ii are thermodynamically less favored by +22.8
and +19.2 kcal·mol–1 compared to their imide isomers 6-i and 7-i, respectively (see ESI Table S10). Furthermore,
the transition state calculated for the uncatalyzed rearrangement reaction f for cyclic isoimides to imides (i.e.,
from 5-ii to 5-i) is very high in energy (~ +57.4 kcal·mol–1, see ESI Table S10), making such rearrangement highly
unlikely to occur. The rearrangement to cyanoacid (reaction e) might be feasible as such a rearrangement
involves a likely lower activation barrier for hydrogen transfer from N to O with simultaneous O-CN bond
rupture. Unfortunately, our attempts in finding an accessible transition state using DFT energy calculations
remained elusive. Therefore, this pathway to cyanoacids as yet can neither be proven nor excluded on
theoretical grounds. However, in all three cases the cyanoacids are thermodynamically favored over the
isoimides.
As a diagnostic tool we conducted an amidocarbonylation experiment with N-methyl-2-PA as substrate (Table 2,
entry 13) under conditions favorable for formation of cyanoacids with PA. As rearrangement from an N-methyl
isoimide to cyanoacid is impossible, it should be possible to identify N-methyl-2-ethylisoimide, if formed in a
reaction mixture, by NMR and/or GLC analysis. Rearrangement to the cyclic N-methyl imide can also be
excluded as such a rearrangement would likely have to surmount a similarly high activation barrier as 5-ii (>50
kcal/mol). However, in the actual experiment N-methyl-2-ethylsuccinimide (and not the corresponding
isoimide) was observed as the exclusive product of cyclo-amidocarbonylation, giving a strong indication that the
isoimides are neither formed as intermediate products to cyanoacids in the amidocarbonylation of PAs. This
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thus suggests that the envisaged intermediate Pd-iminolate in species PdO does not undergo iminolysis of Pd-
acyl (Scheme 4, reaction d) at a sufficiently high rate under the applied mild conditions (60 °C), as this step
apparently involves a too high energy barrier. The reaction system will then rather proceed via the existing
equilibrium with N-coordinated species PdN, and subsequent nucleophilic attack involving a significantly lower
energy barrier to produce exclusively the thermodynamically most stable imide 5-i. As indicated by the DFT
calculated energy differences between isoimides and imides, it can be indeed reasonably assumed that the
activation energy for iminolyis in species PdO as rate-determining step resulting in a ~15 kcal/mol higher-energy
isoimide product will be significantly higher than the activation energy for rate-determining imidolysis in species
PdN forming the thermodynamically most stable imide product (Bell-Evans-Polanyi principle).[37]
Figure 2. Schematic representation of the energies (in kcal/mol) calculated for the various (potential)
carbonylation products of pentenamide.
On the other hand, the absence of isoimide formation with N-methyl-2-PA is also a clear signpost that an
alternative low barrier route to cyanoacids must exist in amidocarbonylation of PAs, which does not involve
isoimides as intermediates. We therefore envisage a direct pathway to cyanoacids via reactions g and h in
Scheme 4. This pathway can be viewed as an intramolecular dehydrating hydroxycarbonylation of PAs.
Dehydration of the amide moiety leads to Pd-acyl bound water, a direct intermediate in subsequent
hydroxycarbonylation of the alkene moiety of PAs. There is precedent of PdII-catalyzed dehydration of primary
amides and for H2O transfer between primary amides and nitriles.[38] Dehydration of the amide moiety likely
involves a sequence of H- and OH transfers from the iminol moiety to the Pd center, but a concerted transfer to
Pd-acyl thus reforming Pd-H together with the carboxylic and nitrile moieties could also be envisaged. The exact
mechanism for dehydrating hydroxycarbonylation of PAs is not known, but it seems reasonable to assume that
the hydrolysis step of the intermediate Pd-acyl species provides a lower energy barrier than the preceding
dehydration of the amide moiety, thereby avoiding water build-up. The alternative two-step process, i.e.
dehydration of PAs and subsequent intermolecular hydroxycarbonylation of pentenenitrile as separate steps, is
less likely to occur because of two reasons. First, in a control experiment the hydroxycarbonylation of
pentenenitrile/H2O mixtures could not be demonstrated with the catalyst systems under the prevailing acidic
catalytic conditions in this work (see ESI). Instead, only traces of imides (5-i, 6-i) and CVA were formed due to
rapid deactivation of the catalytic system by consumption of the co-catalyst HOMs via stoichiometric hydrolysis
of pentenenitrile (producing pentenoic acid and the salt NH4OMs which precipitated from solution), see ESI
Table S1. Second, a build-up of H2O would thus lead to equimolar amounts of pentenenitriles, which were not
observed. Indeed, when the amount of acid was increased to a 1:1 stoichiometry with respect to the substrate
the only product that was observed was adipic acid, i.e., through full hydrolysis and hydroxycarbonylation of the
PA substrate.
In another control experiment (see ESI) 3-cyanopropionic acid (ECA) was exposed to the L3Pd/HOMs catalyst
system under a CO pressure (50 bar) at 105 °C, which resulted in complete conversion to the corresponding
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imide (5i-i) in 16 h, clearly indicating a Pd-catalyzed reverse process from that of Scheme 4. Interestingly, in the
absence of Pd and CO, but in the presence of 10 mol% HOMs only about 10% imide was formed in 16 h.
Although conducted at a higher temperature than the forward reactions reported in Table 2 (60 °C), the result
of this experiment suggests that the reaction pathway represented in Scheme 4 reactions b, g and h likely
provides a reversible pathway from CAs to the thermodynamically more stable imide with a sufficient rate at a
higher reaction temperature. It thus suggests that ECA is a kinetic product under the low temperature
conditions, which consecutively can be converted to the thermodynamically most stable imide 5-i. Thus, when
amidocarbonylation is conducted at higher temperatures, even in the presence of NMP, CAs are not produced
as final carbonylation products (Table 2, entry 12), i.e., consecutive conversion to the more stable imides
prevails under these conditions. The decreased formation of CA’s at low CO pressures, in particular in favour of
5-i (Table 2, entries 8, 11), could be a reflection of the influence of CO binding on the coordination mode of the
pendent amide moiety. Thus less CO present seems to favour N-amide coordination, possibly because a high
concentration of CO prevents the rearrangement from the O-coordinated amide to the thermodynamic N-
coordinated product.
Scheme 4. Reaction scheme explaining the chemoselectivity for the amidocarbonylation of pentenamides; all palladium
species in this scheme are PdII. Displayed here: regioselectivity towards 5-membered Pd-alkyl ring forming ethyl-branched
products (see Scheme 3); weakly coordinated anions(OMs–) associated with catalytic [LPd]+ centre not shown. a) In the
presence of strong acid in diglyme, the amide group coordinates through the N atom (PdN). b) In the absence of strong
acid, or when the acid is quenched by basic solvents such as NMP, the amide can coordinate through the O atom (PdO). c)
‘Ring-closing elimination’ leads to direct formation of the imide product 5-i, and (P-P)Pd0, which is rapidly or concertedly
protonated to reform the active catalyst Pd-H. d) ‘Ring-closing elimination’ may lead to formation of the isoimide 5-ii (an
unstable intermediate), and (P-P)Pd0, which is rapidly or concertedly protonated to reform the active catalyst Pd-H. e) The
unstable intermediate 5-ii rearranges to give the cyanoacid product ECA. f) The rearrangement to indirectly form 5-i is
unlikely because of a large activation barrier due to ring strain. g) Alternative direct pathway to ECA: the O-coordinated
amide can be dehydrated which subsequently leads to h) concerted hydroxycarbonylation of the intermediate cyanoacyl-
Pd-OH2 species.
Consequences for intermolecular amidocarbonylation. Finally, we relate the experimental findings of
intermolecular amidocarbonylation (Table 3) with the mechanistic model we developed in Scheme 4 for the
intramolecular amidocarbonylation of PAs. Clearly the characteristics of inter- and intramolecular
amidocarbonylation must be highly similar. Notably, under acidic conditions the N-coordinated Pd-amide exists
and the catalytic events will lead to imides as the products (Table 3, entry 4). These products are a result of
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nucleophilic attack of the amide substrate of the open chain Pd-C8-acyl. Under quenched-acid conditions (or so
called acid-free conditions in the Beller protocol[16]), similar to the intramolecular version of amidocarbonylation
the existence of O-coordinated Pd amide precursors can lead to coproduction of a C9 carboxylic acid together
with the nitrile derived from the applied amide substrate (Table 3 entries 2, 3 and 5). Such a conversion is likely
to occur via dehydrating hydroxycarbonylation, like the intramolecular version producing cyanoacids from PAs.
However, when using N-methyl acetamide as the nucleophile a mechanism involving an H-transfer process in
the dehydrating process at the Pd center obviously cannot take place. Therefore, under acid-free conditions,
the hypothetical and thermodynamically unfavorable N-methyl-nonanoylmethylisoimide should be formed by
the iminolysis reaction of the Pd-acyl iminolate. However, this N-methyl isoimide was not observed; exclusively
N-acetyl-N-methylnonanamide was formed (Table 3, entry 1). This means that equilibria between O- and N-
coordinated amide-Pd species (analogous to those indicated in Scheme 4) cause a shift in product formation via
the N-coordinated species, thus ultimately exclusively forming the imide product.
Conclusion
We show that Pd-catalyzed intramolecular amidocarbonylation of pentenamides can lead to two types of
isomeric carbonylation products. In the presence of strong acid (pKa << 0), 5- and 6-membered cyclic imides are
formed in high selectivity. However, in the absence of strong acid, or when the strong acid is quenched by
addition of an external amide such as NMP, cyanocarboxylic acids are produced. An NMR spectroscopic study
showed the involvement of several possible modes of amide coordination to a cationic (P-P)PdII center,
depending on the presence or absence of acid. In combination with a catalytic study also involving
intermolecular amidocarbonylation using several primary and secondary amides as substrates it was deduced
that the dependence of the catalytic results on the pH has its origin in the prevailing coordination mode of the
(chelating) amide functionality. In the presence of strong acid imides must be formed via N-coordination of the
amide to PdII. Under neutral conditions, however, the kinetically favored O-coordination of the (chelating)
amide leads to the formation cyanocarboxylic acids. It is proposed that these cyanoacids are formed as kinetic
products by a novel type of Pd catalyzed conversion termed ‘dehydrating hydroxycarbonylation’ of PAs in which
the primary amide functionality is dehydrated at Pd while the formed H2O is concertedly consumed in
hydroxycarbonylation of the PAs alkene moiety. Under elevated temperatures the cyanoacids can be converted
to the thermodynamically more stable imides via the reversed Pd-catalyzed pathway. It is shown that
intermolecular amidocarbonylation applied to separate alkenes and amide nucleophilic reagents as substrates,
proceeds via an analogous mechanistic pathway. With primary amides and under acid-free or acid-quenched
reaction conditions amidocarbonylation of an alkene produces selectively carboxylic acids and nitriles in a 1:1
ratio with high rates. Under acidic conditions, however, N-acyl amides can also be selectively produced from the
same substrates. Experiments with N-alkylated amides as substrate have been diagnostic in developing
plausible mechanistic schemes of Pd-catalyzed cyclo-amidocarbonylation of (functional) alkenes under both
acidic and acid-free conditions.
In the presence of a strong acid as a co-catalyst double-bond isomerization appears to be much faster than
ultimate product formation, therefore opening up the possibility to selectively produce linear imides from
internal alkenes and both primary and secondary amides as the nucleophiles. In the case of ring-closing
amidocarbonylation starting from pentenamides, however, the chelation strength of the amide functionality to
palladium determines which product is formed. Because the chelation strength becomes smaller with increasing
size of the palladacycle, only 5-i and a small amount of 6-i were obtained. In conclusion, we have overcome two
of the challenges of the bio-based synthesis of 7-i: chemoselectivity to form imides and fast double-bond
isomerization. The last challenge is to overcome the regioselectivity induced by the chelation of the pendent
amide. To prevent this unfavorable chelation is subject of further study.
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Experimental
General. A glovebox of M. Braun Inert gas-System GmbH, Germany, was used for storing and handling of air-
sensitive phosphane ligands. All reaction preparations and manipulations were performed using standard
Schlenk techniques under an argon atmosphere (i.e. catalytic procedure, collecting, drying, degassing solvents).
The stainless steel autoclave reactors (100 mL) were of HEL Limited, UK, equipped with magnetic stirrer,
pressure transducer and temperature controlling thermocouple. A Hewlett Packard HP6890 Series auto-sampler
GC system was used for regular GC analysis (FID detector), together with a column from Agilent (HP-1MS UI; 30
m, 0.25 mm i.d., 1 μm film thickness) using helium as carrier gas. The separation of imides 5-i, 6-i, and 7-i as well
as cyanoacids 5-cyanovaleric acid (CVA), 2-methyl-4-cyanobutyric acid (MCA) and 2-ethyl-3-cyanopropionic acid
(ECA), was performed on a Varian CP.3800 GC, with an Alltech column (ATTM-WAX; 30 m, 0.53 mm, 2 μm film
thickness), using helium as carrier gas. GC-MS analysis were carried out on an Agilent technologies 7820A GC
system series coupled with an Agilent technologies 5975 series GC-MSD system, and a column from Agilent
(DM-5MS UI, 30 m, 0.25 mm, 1 μm film thickness), using helium as carrier gas. GC-yields were calculated using
undecane as internal standard. The approximation was made that 5-i, 7-i, and the corresponding cyanoacids,
since they show the same empirical formula, had the same response factor as 6-i with the FID detector. Nuclear
magnetic resonance spectra were recorded on a Bruker DPX300 (300MHz) spectrometer, on a Bruker AV-400
(400 MHz) spectrometer, or on a Bruker AV-500 (500 MHz) spectrometer. Chemical shifts (ppm) are given
relative to solvent or to TMS. High resolution mass spectra (HRMS) were recorded on LTQ-orbitrap mass
spectrometer (Thermo Fisher Scientific, Waltham, USA). The data are given as mass units per charge (m/z). For
preformed Pd(L)(dba) and imides the ionization technique used was is ESI (Electro Spray Ionization). HRMS of
the cyanoacids were also performed with APCI (Atmospheric Pressure Chemical Ionization). Purification of the
products was conducted with technical grade solvents and silica gel 60, 40-63 µm (Screening Devices bv).
Gases. Carbon monoxide and dihydrogen were purchased from Linde.
Chemicals. Pd(dba)2 and Pd(OAc)2, were purchased from Sigma-Aldrich. Pd(TFA)2 and L1 (dtbpx) were
purchased from Strem. The cage ligands L2, L3, L4 were donated by Shell (where they were previously
synthesized according to literature procedures).[39] Pentenoic acids (trans 2-pentenoic acid, 3-pentenoic acid, 4-
pentenoic acid), used for the synthesis of pentenamide substrates (PAs), were purchased from Sigma Aldrich (2-
and 3-PA) and Alfa Aesar (4-PA). Undecane (internal standard) was purchased from Merck. All other reagents
(acids, promoters) were purchased from Sigma-Aldrich. The liquids were degassed and dried over molecular
sieves, and stored together with the solids in a glovebox under argon. 2-Methyl glutarimide (6-i) was purchased
from Novochemy as a pure authentic sample, which allowed a GC calibration vs. undecane in GC. Adipimide
(7-i) was purchased from Uorsy.
Substrates. 3-PA, 4-PA were synthesized as reported.[8-9] The same procedure was utilized to produce 2-PA
(from trans-2-pentenoic acid). After synthesis of each pentenamide the obtained white solid was dissolved in a
minimum amount of dichloromethane and reprecipitated with cold hexane (–20 °C). The crystalline solid was
then filtered, washed with cold hexane, and dried in vacuo. The resulting white powder was ultimately filtered
over a pad of basic alumina (dichloromethane was used as eluent) to provide us with analytically pure
pentenamides.
Typical batch autoclave reaction with the catalytic system comprising Pd(L)(dba) + 30 eq HOMs
The substrates 2-, 3-, or 4-PA (99.1 mg, 1 mmol) were weighed in a glass insert (containing an oven-dried
stirring bar) which was subsequently introduced into an autoclave reactor. The autoclave was tightly closed and
subsequently filled with argon, using a Schlenk line connected to one of the valves of the autoclave. In parallel,
Pd(L1)(dba) (4.4 mg, 5 µmol) was dissolved in dried and degassed diglyme (2.5 mL) in a Schlenk flask (in a
glovebox under argon). Methane sulfonic acid (9.8 µL, 0.15 mmol) was added to this yellow solution, which
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turned immediately red. Undecane (1.185 mmol, 0.250 mL) was then added as an internal standard and the
solution was eventually transferred to the autoclave via cannula (through another valve, under a continuous
flow of argon). After 5 minutes at RT the autoclave was flushed with CO, and then pressurized with 50 bar of CO.
The reaction mixture was heated to 100 °C (within about 30 min) under stirring at 500 rpm. All reaction
conditions of the catalytic process were controlled by computerized software panels. After standing for 16
hours at this temperature, the autoclave was cooled down to room temperature over approximately one hour
and subsequently vented to atmospheric pressure. Alterations to this procedure are explained in the ESI.
Acknowledgements
This research was performed within the framework of the CatchBio program. We gratefully acknowledge the
support of the SmartMix Program of the Netherlands Ministry of Economic Affairs and the Netherlands Ministry
of Education, Culture and Science. Royal Dutch Shell plc is kindly acknowledged for a generous donation of
phosphane ligands. We are grateful to Gerwin K. Spijksma for mass spectrometry measurements, Fons Lefeber
and Dr. Karthick B. Sai Sankar Gupta for their help with the NMR studies and to Jos van Brussel for GC expertise.
Supporting information
Supporting information is available: synthetic procedures of the complexes, synthesis and characterization of
the products and catalytic procedures are supplied. Tables describing optimization of product formation are
supplied (Table S2-S9). NMR spectra of the coordination of acetamide to L3PdII are supplied (Figures S2-S7).
Computational details on the DFT calculations of products and intermediates are supplied (Tables S10–13).
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10.1002/cctc.201700345
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Table of Contents
A new isomerizing ring-closing amidocarbonylation reaction is reported. From an NMR study it was deduced
that N-coordination of the amide moiety is responsible for a high selectivity to cyclic imide products, whereas
O-coordination of the amide functionality leads to the formation of cyanoacids.
17
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