Bis-Alkoxycarbonylation of Acrylic Esters and Amides for the Synthesis of 2-Alkoxycarbonyl or 2-Carbamoyl Succinates

Article abstract of DOI:10.1002/adsc.201900918

The first example of the bis-alkoxycarbonylation of acrylic esters and acrylic amides, leading to differently substituted 1,1,2-ethanetricarboxylate compounds and 2-carbamoylsuccinates respectively, is reported. The catalyst is formed in situ by mixing Pd

Full text of DOI:10.1002/adsc.201900918

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DOI: 10.1002/adsc.201900918
Very Important Publication
Bis-Alkoxycarbonylation of Acrylic Esters and Amides for the
Synthesis of 2-Alkoxycarbonyl or 2-Carbamoyl Succinates
Diego Olivieri,a Riccardo Tarroni,a Nicola Della Ca’,b Raffaella Mancuso,c
Bartolo Gabriele,c Gilberto Spadoni,d and Carla Carfagnaa,*
a
Department of Industrial Chemistry “T. Montanari”, University of Bologna, Viale Risorgimento 4, 40136 Bologna (BO), Italy
E-mail: carla.carfagna@unibo.it
Department of Chemistry, Life Sciences and Environmental Sustainability (SCVSA), University of Parma, Parco Area delle
b
Scienze 17A, 43124 Parma (Italy)
Department of Chemistry and Chemical Technologies, University of Calabria, Via P. Bucci 12/C, 87036 Arcavacata di Rende
c
(CS), Italy
d
Department of Biomolecular Sciences, University of Urbino “Carlo Bo”, Piazza Rinascimento 6, 61029 Urbino (PU), Italy
Manuscript received: July 24, 2019; Revised manuscript received: September 13, 2019;
Version of record online: ■■■, ■■■■
Supporting information for this article is available on the WWW under https://doi.org/10.1002/adsc.201900918
Abstract: The first example of the bis-alkoxycarbonylation of acrylic esters and acrylic amides, leading to
differently substituted 1,1,2-ethanetricarboxylate compounds and 2-carbamoylsuccinates respectively, is
reported. The catalyst is formed in situ by mixing Pd(TFA)2 (TFA=trifluoroacetate) and the ligand bis(2,6-
dimethylphenyl)butane-2,3-diimine. The reaction, that proceeds using p-benzoquinone as oxidant and p-
toluenesulfonic acid as additive, has been applied to variously substituted electron-poor alkenes, employing
°
different alcohols as nucleophiles, under very mild reaction conditions (4 bar of carbon monoxide at 20 C).
Remarkably, this catalytic system is able to promote the carbonylation of both the β- and the generally
unreactive α-positions of acrylic esters and amides, allowing the formation of bis-alkoxycarbonylated products
in good to excellent yields (up to 98%). The trend of reactivity, observed with the different electron-deficient
olefins, has been rationalized on the basis of the proposed catalytic cycle and DFT calculations.
Keywords: aryl α-diimine ligands; carbonylation; electron-deficient compounds; oxidative carbonylation;
palladium
Introduction
deficient olefin with the catalyst.[7a–b] In addition, the
alkoxycarbonylation of electron-poor alkenes is re-
Palladium-catalyzed carbonylation reactions represent stricted to the β-position with respect to the electron-
a very powerful methodology that converts inexpen- withdrawing group (EWG) of the olefin (Scheme 1a),
sive feedstocks, such as carbon monoxide, alkenes or while the α-carbon turns out to be not enough
alkynes, into useful carbonylated compounds like nucleophile to allow the prompt insertion of the
aldehydes, esters or ketones.[1] In the last decade many carbonyl group.[8] To our knowledge, only Nozaki et al.
contributions have been made in this area utilizing an showed, in the regiocontrolled copolymerization proc-
oxidizing agent[2] and an alcohol as nucleophile,[3] for ess of methyl acrylate with CO, that it is possible to
the synthesis of high added value esters. In spite of the carbonylate both the α- and the β- positions of acrylic
remarkable advances made in the field of alkoxycarbo- esters, using a phosphineÀ sulfonate palladium catalyst
nylation and bis-alkoxycarbonylation reactions of (Scheme 1b).[9] Recently, we have developed a very
terminal[4] and internal olefins,[4a,5] so far, the carbon- efficient catalytic system able to promote the bis-
ylation of electron-poor alkenes has not been exten- alkoxycarbonylation of terminal alkenes,[4e] 1,2-disub-
sively developed and remains a major challenge.[4a,6] stituted olefins[5a] and internal alkynes.[10] The catalyst
This is probably due to the low coordination ability of was based on the combination of a palladium salt with
the carbonÀ carbon double bond[7] and to the possible bis(aryl)acenaphthenequinonediimine (BIAN) or 1,4-
interaction of the functional group of the electron- diaryl-2,3-diazabutadiene ligands. Similar Pd(II) com-
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Table 1. Bis-alkoxycarbonylation of methyl acrylate 2a. Effect
of the ligands 1a–f and of the catalyst loading.
Entry[a] Catalyst Loading (mol%)[b] Ligand Conversion (%)[c]
1a–1f
1
2
3
4
5
6
7
8
9
3
0.5
0.5
2
2
2
2
2
2
–
< 5
22
13
90
45
90
85
37
< 5
1a
1c
1a
1b
1c
1d
1e
1f
Scheme 1. Mono- and bis-carbonylation of electron-deficient
olefins.
plexes bearing aryl α-diimine ligands were also used
by us in the copolymerization of styrenes with CO,
yielding copolymers with a high degree of tacticity.[11]
In this work, we have studied the possibility to
effectively realize the bis-alkoxycarbonylation of elec-
tron-deficient olefins to give 2-EWG-substituted succi-
nates, employing palladium/aryl α-diimine complexes
as catalysts, as shown in Scheme 1c.
Succinic acid and their derivatives find applications
in many industrial fields,[12] including pharmaceutical
chemistry.[13] Moreover, the envisioned bis-alkoxycar-
bonylation of electron-deficient olefins such as acrylic
esters and amides could enable the direct synthesis of
[a] Reaction performed in autoclave at PCO =4 bar, with methyl
acrylate 2a (2 mmol-scale), Pd(TFA)2 0.5–2 mol%, ligands
1a–f 0.55–2.2 mol%, using 2 mol% of p-TSA and 1.5 equiv.
of BQ, in 7:1 MeOH/THF (0.5 M) as the reaction medium,
for 67 h.
[b] Pd(TFA)2/Ligand=1:1.1.
[c] Determined by direct H NMR analysis on a sample of the
1
reaction mixture.
1,1,2-ethanetricarboxylates and 2-carbamoylsuccinates, (TFA)2 as catalyst (entry 1). Employing ligands 2,6-
key building blocks for medicinal[14] and organic[15] dimethyl aryl α-diimine 1a or 9-anthryl α-diimine 1c
chemistry.
together with 0.5 mol% of Pd(TFA)2, conversions of
22% and 13% were achieved respectively, with the
selective formation of trimethyl ethane-1,1,2-tricarbox-
ylate 3a (entries 2 and 3). After these initial encourag-
Results and Discussion
We started our investigation on the bis-alkoxycarbony- ing results, we decided to rising up the catalyst loading
lation of electron-poor alkenes, choosing methyl to 2 mol%, obtaining 90% of olefin conversion with
acrylate 2a as the model substrate (Table 1). We have both ligands 1a and 1c (entries 4 and 6). Instead, using
previously underlined the importance of the ortho- ligand 1b, where the two methyl groups of the
disubstitution on the aryls of α-diimine ligands to backbone were replaced with two hydrogen atoms,
promote an efficient olefin bis-alkoxycarbonylation only 45% of methyl acrylate reacted (entry 5). With
reaction, under mild reaction conditions.[4e,5a] Here a the o-dimethyl BIAN ligand 1d, the result was just
further investigation on the effects of the backbone slightly less satisfactory with respect to those obtained
structure and on the nature of the ortho-substituents with ligands 1a and 1c (entry 7). On the other hand,
has been performed testing ligands 1a–f (Table 1). As the presence of bulky isopropyl groups on the aromatic
expected, no reaction was observed using only Pd
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rings (ligand 1e) drastically reduced the conversion
(entry 8).
Employing the ligand 1f, with fluorine substituents
in ortho and para positions, the reaction did not
proceed at all (entry 9), probably due to the low
basicity of the ligand that makes the catalyst less
stable.[16] These results clearly indicate that not only
the electronic character and the steric hindrance of the
ortho-substituents of the aromatic rings, but also the
rigidity of the resulting catalysts, influenced by the
backbone,[17] greatly affected the reactivity.[18]
Scheme 2. Reactivity of vinyl ketone 8, in our bis-alkoxycarbo-
Since further experiments, carried out to optimize
the other parameters of the reaction, did not lead to
appreciable improvements (Table S1, SI), we decided
nylation conditions, using BnOH as nucleophile.
to continue our investigation applying the catalytic alkoxycarbonylated product was detected (entry 4). In
system indicated in entry 4 of Table 1. With the this case, the olefin mainly underwent a methoxylation
catalyst formed in situ from the easily synthesizable reaction leading to the formation of 1-methoxyoctan-3-
ligand 1a and Pd(TFA)2, the bis-alkoxycarbonylation one product 11a together with other unidentified
reaction proceeded in the presence of 1.5 equivalents byproducts. (Table S2, SI). Interestingly, using benzyl
of p-benzoquinone (BQ) and 2 mol% of p-TSA, in alcohol as nucleophile, the mono-carbonylated benzyl
methanol/THF 7:1 (0.5 M) as reaction medium, under 4-oxononanoate product 12b was formed in 1:1 ratio
°
a CO pressure of 4 bar at 20 C. These conditions were with the corresponding mono-alkoxylated compound
then applied to various conjugated polar alkenes, in 11b (Scheme 2 and pages S3–S5, SI). Acrylonitrile 9
order to get preliminary insights on the generality of and phenyl vinyl sulfone 10 were unreactive under
the process (Table 2).
these conditions (entries 5 and 6, Table 2). Notably,
conversions in Table 2 seem to be correlated to the
nature of the electron-withdrawing group. In particular,
olefins bearing an EWG group with a lower electron-
attractor character gave higher yields in the desired
product.
Table 2. Bis-methoxycarbonylation of various electron-defi-
cient olefins.
On the basis of these results, our previous mecha-
nistic investigations[11,20,21] and literature data,[22,23,9] we
propose the catalytic cycle depicted in Scheme 3,
which allows to rationalize the observed reactivity of
electron deficient olefins. According to a generally
accepted mechanism, nucleophilic attack of the alcohol
on complex A, which has been recently isolated and
characterized,[5a] affords the active species B.[22,24]
The subsequent insertions of CO[25] and of the
electron-deficient olefin lead to the 5-membered
palladacycle intermediate E.[9,11,20–23,26,27] Further CO
insertion gives complex F,[9a,21] which then undergoes
nucleophilic displacement by the alcohol, to afford the
final bis-alkoxycarbonylated product and the palladium
hydride intermediate G. The latter is finally oxidized
by p-benzoquinone with regeneration of the active
catalyst B.[28,29] Intermediates similar to E and F have
been previously isolated by Nozaki et al. with
phosphineÀ sulfonate ligands[9] and by us with aryl α-
diimine ligands.[11,27] Ancillary experiments were con-
ducted to further support the first steps of the proposed
Entry[a] Olefin EWG
Conversion (%)[b] Yield (%)[c]
1
2
3
4
5
6
4g
2a
6
8
9
CONMe2
COOMe
P(O)(OEt)2
C(O)C5H11
CN
>98
90
95
78
25
0
32
100[d]
<5
<5
–
–
10
SO2Ph
[a] Reaction performed in autoclave at PCO =4 bar, with olefin
(2 mmol), Pd(TFA)2 (2 mol%), ligand 1a (2.2 mol%), p-TSA
(2 mol%) and BQ (1.5 equiv.), in 7:1 MeOH/THF (4 mL) as
the reaction medium, for 67 h.
1
[b] Determined by H NMR analysis of the reaction crude.
[c] Isolated yields after column chromatography.
[d] The olefin 8 was mainly converted into 1-methoxyoctan-3-
one 11a.
Interestingly, a complete conversion was achieved catalytic cycle, but the low solubility of the complex
with N,N-dimethylacrylamide 4g, which resulted to be A[5a,30] and the high instability of the formed species,
more reactive than methyl acrylate 2a (entries 1 and 2, precluded the isolation of the intermediates (see pag.
Table 2). The diethyl vinyl phosphonate 6 gave less S6, SI). However, after one catalytic cycle, in a
satisfactory results (entry 3),[19] while with the α,β- stoichiometric reaction with olefin 2a, the formation
unsaturated ketone 8, no trace of the desired bis- of trifluoroacetic acid and hydroquinone in quantitative
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Previous investigations, aimed at rationalizing the
low reactivity of electron-deficient olefins in copoly-
merization reactions,[6–9] allowed to draw some impor-
tant conclusions, which can be summarized in the
following three points, i) the coordination ability of the
CÀ C double bond of olefins is reduced by the presence
of an electron-withdrawing group[7] (Scheme 3, inter-
mediate D), ii) a competitive coordination by the
heteroatom-containing functional group of the olefin
can take place (intermediate D’)[7a–b] and iii) the second
CO insertion, forming the intermediate F, is inhibited
by the low nucleophilicity of the carbon, bearing the
EWG group and linked to the Pd center in complex
E.[8,9]
Scheme 3. Proposed catalytic cycle. EWG=electron-withdraw-
ing group, BQ=p-benzoquinone and H2Q=1,4-hydroquinone.
amount was possible to detected, together with product
3a (Scheme S2, SI). The alternative mechanism, which
involves β-hydride elimination from intermediate E
leading to a mono-carbonylated compound of the type
EWGÀ CH=CHÀ COOR and its successive alkoxycar-
bonylation, has been excluded since, utilizing the
dimethyl fumarate 2f as substrate, the formation of the
expected carbonylated product 3a was not observed
(Scheme 4).
Figure 1. Gibbs free energies (in kJ/mol) diagrams relative to
the insertion of the second CO molecule, for the olefins listed in
Table 2. The energy of the open chain intermediate E1, with the
CO coordinated to the Pd centre, has been taken as common
reference.
Scheme 4. Study on the alternative mechanism involving β-H
elimination in the intermediate E.
In order to assess whether such effects were also at
work in our catalytic cycle, and if they were
responsible for the different reactivity of the EWG-
substituted alkenes shown in Table 2, we performed
some preliminary DFT calculations. In particular, we
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focused our attention on the insertion of the second
molecule of CO, analyzing in detail the energies of the
intermediates that are part of the process.
Table 3. Scope of the bis-alkoxycarbonylation reaction of
acrylic esters.
In addition, to have a first evaluation of the EWG
capability to coordinate the Pd center, we have
calculated the Natural Population Analysis (NPA)
partial charges on the oxygen of the carbonyl group of
the EWGs (see Table S3, SI). For the olefins of
Table 2, we have then calculated the energy of the
open-chain intermediate E1, in which a second CO
molecule is coordinated to Pd, the energy of the 6-
membered palladacycle complex E3, where the CO is
inserted, and the energy of the relative transition state
E2(TS) (Figure 1). The intermediates E1 and E3, not
explicitly reported in the proposed catalytic cycle, are
the expected species leading to the formation of
intermediate F starting from the 5-membered pallada-
cycle complex E (Scheme 3). The free energy values
ΔG� of E2(TS) for phenyl vinyl sulfone 10 (95.1 kJ/
mol) and for acrylonitrile 9 (82.7 kJ/mol) are the
highest among those calculated, while for N,N-dimeth-
ylacrylamide 4g (68.1 kJ/mol), methyl acrylate 2a
(63.5 kJ/mol) and diethyl vinyl phosphonate
6
(59.4 kJ/mol) the values are similar and lower by at
least 15 kJ/mol. The unreactivity of sulfone 10 and
acrylonitrile 9 (Table 2, entries 6 and 5) was in agree-
ment with both the very high ΔG� values of E2(TS)
and the high coordination ability of sulphonic oxygens
and of the À CN group towards Pd (entries 14 and 13,
Table S3). Indeed, it has been found, in Pd-catalyzed
insertion copolymerizations, that the inertia of acryl-
onitrile can be ascribed to a strong σ-bond between the
nitrogen atom and palladium, making the π-coordina-
tion less likely.[7a] In a similar manner, the low
phosphonate conversion (Table 2, entry 3) could be
justified by the high coordination ability of the
phosphonic oxygen (entry 11, Table S3), even if the
ΔG� value was comparable with those of the much
more reactive olefins 2a and 4g. Using the acrylic
ester 2a and the acrylic amide 4g, nearly quantitative
conversions were achieved (Table 2, entries 2 and 1).
Accordingly, the values of ΔG� and of the partial
charges on the carbonyl oxygen were similar (entries 1
and 10, Table S3) and in line with a good productivity.
The higher reactivity of 4g could be attributed to the
greater stability of intermediate E3 (Figure 1). For the
vinyl ketone 8, the value of ΔG� would be potentially
favorable but, owing to its different reactivity, this step
cannot be reached. Actually, the main problem with
the olefin 8 (Table 2, entry 4) was the preferential
competitive alkoxylation reaction to afford compounds
11. However, using benzyl alcohol as nucleophile, the
concomitant formation of the mono-carbonylated prod-
uct 12b (Scheme 2 and Table S2, entry 4) suggests that
the coordination and insertion of olefin 8 is possible.
Although in this case it has not been possible to obtain
the bis-alkoxycarbonylated derivatives, this interesting
[a] Reaction performed in autoclave at PCO =4 bar, with olefins
2a–2e (2 mmol), Pd(TFA)2 (3 mol%), ligand 1a (3.3 mol%),
p-TSA (2 mol%) and BQ (1.5 equiv.), in 7:1 R1OH/THF
(4 mL), for 67 h.
[b] Isolated yields after column chromatography.
[c] Incomplete conversions (%) in brackets.
[d] Reaction performed with 5 mol% of catalyst loading.
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Table 4. Scope of the bis-alkoxycarbonylation reaction of
acrylic amides.
[a] Reaction performed in autoclave at PCO =4 bar, with olefins
4a–4g (2 mmol), Pd(TFA)2 (2 mol%), ligand 1a (2.2 mol%),
p-TSA (2 mol%) and BQ (1.5 equiv.), in 7:1 R1OH/THF
(4 mL), for 67 h.
[b] Isolated yields after column chromatography.
[c] Incomplete conversions in brackets.
Reaction performed with 5 mol% of catalyst loading at 50 C.
[d]
°
reactivity will be further studied to selectively obtain
γ-ketoesters.
The process described here represents the first
example of bis-alkoxycarbonylation of electron-defi-
cient olefins. In fact, although several examples of 5-
membered palladacycles of type E with diverse ligands
and various electron-poor alkenes have been
reported,[23] the subsequent CO insertion was not
observed.
We then proceeded with the evaluation of the scope
of this unprecedented bis-alkoxycarbonylation reac-
tion. Differently substituted acrylic esters were first
tested (Table 3). The catalyst loading was raised to
3 mol%, and this enabled the complete conversion of
methyl acrylate 2a into product 3a (entry 1). Excellent
isolated yields of compounds 3b and 3c were also
obtained starting from benzyl acrylate 2b and phenyl
acrylate 2c respectively (entries 2 and 3). The for-
mation of products 3d and 3e in high yields,
demonstrates that this process can be successfully
applied to acrylic esters bearing a long alkyl side chain
or a sterically demanding substituent[31] on the oxygen
(entries 4 and 5). Using the bulky and less nucleophilic
isopropanol in place of methanol, the formation of the
corresponding compound 3aa was less satisfactory
(entry 6, Table 3), while employing benzyl alcohol the
yield of the product 3ab was still high (entry 7,
Table 3).
Regarding the more reactive acrylic amides, after a
further optimization study (Table S5, SI), we pro-
ceeded using the same conditions employed for acrylic
esters, but reducing the catalyst loading to 2 mol%.
Besides acrylamide 4a, differently substituted N-
alkylacrylamides and N,N-dialkylacrylamides were
tested, and, in all cases, the corresponding 2-carba-
moylsuccinates 5a–5gc were formed with complete
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selectivity and high isolated yields (Table 4). Note-
worthy, the bulky tert-butyl acrylamide 4d gave 78%
yield of the product 5d with 85% of conversion.
Table 6. Bis-methoxycarbonylation of acrylic amides using
1 mol% of catalyst loading.
Notably, the hydroxyl group, present in the side
chain of the olefin, such as in N-(2-hydroxyethyl)
acrylamide 4e, was well tolerated, and the bis-
alkoxycarbonylated product 5e was selectively ob-
tained in nearly quantitative yield (entry 5, Table 4).
Products 5f and 5g, bearing a dialkyl substituted
nitrogen, were obtained in excellent yields. The use of
isopropanol or benzyl alcohol as nucleophiles led to
excellent yields of the products 5ga and 5gb (entries 8
and 9), while in the presence of the more sterically
hindered tert-butyl alcohol, the corresponding product
5gc was isolated with a satisfactory selectivity, by
rising up the catalyst loading to 5 mol% and increasing
Entry[a]
Olefin 4
R2
R3
Conversion (%) [b]
1
2
3
4
4a
4b
4c
4g
H
H
H
H
90
60
82
68
iPr
Ph
Me
Me
[a] Reaction performed in autoclave at PCO =4 bar, with olefins 4
(2 mmol), Pd(TFA)2 (1 mol%), ligand 1a (1.1 mol%), p-TSA
(2 mol%) and BQ (1.5 equiv.), in 7:1 MeOH/THF (4 mL) as
the reaction medium, for 67 h.
[32]
°
the temperature to 50 C (entry 10, Table 4).
Un-
[b] Determined by H NMR analysis of the reaction crude.
1
fortunately, acrylates or acrylic amides bearing a
methyl or a phenyl group in α- or β- positions were
unreactive (Table S4, SI).
Finally, in order to better appreciate the influence increases, the reactivity of the olefin gradually
of the substituents in acrylic esters and in acrylic decreases.
amides, some of the reactions described above were
However, from the observation of the molecular
tested at 1 mol% of catalyst loading (Table 5 and 6). models based on theoretical calculations, it appears
that this trend is not so much dictated by steric effects,
but rather derives from an increased inductive effect of
the substituents on the esteric or amidic carbonyl. This
tends to increase the partial charge on the oxygen,
Table 5. Bis-methoxycarbonylation of acrylic esters using
1 mol% of catalyst loading.
making the coordination to palladium more likely
(Table S3), resulting in catalyst partial deactivation.
Conclusion
Entry[a]
Olefin 2
R2
Conversion (%)[b]
Despite the low reactivity of electron-deficient olefins
in carbonylation reactions, the first bis-alkoxycarbony-
lation of acrylic esters and acrylic amides, leading to
the synthesis of the respective bis-carbonylated prod-
ucts was successfully developed. The catalytic system
is constituted by Pd(TFA)2 as palladium source, the
easily affordable aryl α-diimine ligand 1a, p-benzoqui-
none as oxidant and p-toluenesulfonic acid as additive.
The reaction proceed under particularly mild condi-
1
2
3
4
2a
2c
2d
2e
Me
Ph
56
28
47
24
(CH2)17CH3
tBu
[a] Reaction performed in autoclave at PCO =4 bar, with olefins 2
(2 mmol), Pd(TFA)2 (1 mol%), ligand 1a (1.1 mol%), p-TSA
(2 mol%) and BQ (1.5 equiv.), in 7:1 MeOH/THF (4 mL) as
the reaction medium, for 67 h.
°
tions (4 bar of CO at 20 C) and different alcohols can
[b] Determined by H NMR analysis of the reaction crude.
1
be used as nucleophiles. Slight changes on the ligand
structure produced a dramatic effect on the perform-
ance of the catalytic system. From the screening
The results confirmed again the higher reactivity of carried out, the importance of the presence of methyl
amides respect to esters in this bis-alkoxycarbonylation substituents both on the ortho- positions of the aryl
reaction. Indeed, while with acrylic esters the con- rings and on the backbone of the ligand was evidenced,
versions range was between 24% and 56%, with confirming the superiority of ligand 1a. The resulting
acrylic amides 4a and 4c the conversions are almost blocked conformation of the catalyst with ligand 1a
complete and resulted to be 90% and 82% respectively. favors the correct approach of the reagents to the
Furthermore, it is evident that the size of the catalytic center, increasing the productivity. On the
substituents negatively affected the reactivity. In other hand, the presence of bulky isopropyl groups in
particular, as the size of the substituents on the oxygen ortho or of fluorine substituents in ortho and para
of acrylic esters or on the nitrogen of acrylic amides positions of the aryls drastically reduces the conver-
sion.
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(Hz). ESI-MS spectra were recorded on Waters Micromass ZQ
4000, using electrospray ionisation techniques, with samples
dissolved in MeOH. Carbon monoxide (Cp grade 99.99%) was
supplied by Air Liquide. The p-benzoquinone was purchased by
Sigma-Aldrich and was filtered off a plug of silica gel washing
with CH2Cl2, obtaining a yellow solid after dried up in vacuum
the solution. Olefins 2a–2e, 4a–4g and 6, 8–10 were purchased
from TCI or Fluorochem. Olefin 2f was purchased from Sigma-
Aldrich. The olefins 2a–2c, 2e, 4e–4g, 6, 8–10 were filtered
off a plug of neutral Al2O3 and used without further purification.
The olefins 2d, 2f and 4a–4d were used without further
purification. Anhydrous THF was distilled from sodium
benzophenone, methanol was distilled from Mg(OMe)2. Iso-
Our catalytic system is able to promote the selective
carbonylation of both the β- and the generally non-
reactive α-positions of acrylic esters and acrylic
amides, leading to the synthesis of 1,1,2-ethanetricar-
boxylate compounds and 2-carbamoylsuccinates re-
spectively in excellent yields, up to 98%. Remarkably,
the reaction can be successfully applied to a wide
range of acrylates and acrylamides bearing different
types of substituents on the oxygen or on the nitrogen
respectively. High productivity has been achieved both
with sterically demanding substituents and with sub-
stituents showing a different electronic character.
Using isopropanol or benzyl alcohol as nucleophiles, propanol, benzyl alcohol and tert-butyl alcohol were dried over
molecular sieves (Alfa Aesar, 4 Å, 1–2 mm, beads). Pd(TFA)2
was purchased by Flurochem, Pd(PhCN)2Cl2 was purchased by
Sigma-Aldrich and both were weighted in an analytical balance
without excluding moist and air. All other chemicals were
purchased from Sigma-Aldrich and used without further
purification. The ligands 1a–b and 1d–e were synthesized
according to a previously reported procedure,[33] as well as the
ligand 1f.[34] The ligand 1c was synthesized according to a
procedure developed by our group.[11]
instead of methanol, productivity is still very good. To
assess the generality of our bis-alkoxycarbonylation
process various conjugated polar alkenes, having
different electron-withdrawing groups, have been
tested.
The resulting trend of reactivity was rationalized on
the basis of the proposed catalytic cycle and supported
by DFT calculations. These studies suggest that two
main factors determine the course of our bis-alkox-
ycarbonylation: i) the competition between the CÀ C
double bond and the EWG group of the olefins for the
coordination to the Pd catalytic center and ii) the
transition state energy for the insertion of the second
carbonyl group. Finally, to better appreciate the
influence of the substituents within the series of acrylic
esters and amides, the catalyst loading was lowered to
1%, obtaining a scale that highlights the greater
reactivity of the amides. Moreover, although the size
of the substituents, on the oxygen or on the nitrogen,
negatively influences the reactivity of the olefins, it
seems that this is mainly due to the inductive effect of
the substituents on the esteric or amidic carbonyl,
making it more inclined to coordinate to palladium.
Further studies, including DFT calculations, are in
progress in order to get more insights into this
remarkable reactivity and to better understand the key
steps of the proposed mechanism.
Computational Details: DFT calculations have been performed
using the ORCA 4.01 suite of quantum chemistry programs.[35]
Geometry optimizations and free energy calculations (at 298 K)
were done with the small def2-TZVP basis[36] and the Becke-
Perdew functional.[37] Additional single point energy calcula-
tions with the larger def2-QZVPP basis[36] and the M06
functional[38] were performed at the previously optimized geo-
metries. Single point energies were eventually amended by
inclusion of solvation effects[39] and dispersion interactions.[40]
The final energy of each structure, used to evaluate the relative
free energies of the various products and intermediates, was
built by summing the difference between the def2-TZVP
electronic and free energies to the def2-QZVPP single point
electronic energy. Natural Population Analysis[41] (NPA) has
been performed using the JAMPA 1.04 package.[42]
General Procedure for the Bis-Alkoxycarbonylation
Reaction of Electron-Deficient Olefins
In a nitrogen flushed Schlenk tube, equipped with a magnetic
stirring bar, the respective olefin 2, 3, 6, 8–10 (2 mmol) and
methanol MeOH (3.5 mL) were added. The mixture was left
under stirring for 10 min. In another nitrogen flushed Schlenk
tube, equipped with a magnetic stirring bar, the Pd(TFA)2
(13.3 mg, 0.04 mmol or 19.9 mg, 0.06 mmol) and THF
(0.5 mL) were added. After the mixture turned in a red/brown
color (25 min), the ligand 1a (12.8 mg, 0.044 mmol or 19.3 mg,
0.066 mmol) was added. The mixture was left under stirring for
20 min, turning in a dark orange color. The olefin solution and
the formed catalyst were injected in sequence in a nitrogen
flushed autoclave, equipped with a magnetic stirring bar,
containing p-benzoquinone (325 mg, 3 mmol) and p-TSA·H2O
(7.6 mg, 0.04 mmol). After 10 min, the autoclave was flushed
three times with CO and pressurized with 4 bar of carbon
Experimental Section
General Methods and Materials
All reactions were carried out under nitrogen atmosphere with
dry solvents under anhydrous conditions, in a stainless steel
autoclave, by using Schlenk technique. Reactions were moni-
1
1
tored by H NMR taking a sample of the crude mixture. H
NMR and 13C NMR were recorded on a Bruker Avance 400
spectrometer (1H: 400 MHz, 13C: 101 MHz), using CDCl3 as
solvent. Chemical shifts are reported in the δ scale relative to
1
residual CHCl3 (7.26 ppm) for H NMR and to the central line
of CHCl3 (77.16 ppm) for 13C NMR. 13C NMR were recorded
with 1H broadband decoupling. The following abbreviations
were used to explain the multiplicities: s=singlet, d=doublet,
t=triplet, q=quartet, hept=heptet, m=multiplet, dd=double
doublets, b=broad. Coupling constants (J) are reported in Hertz
°
monoxide. The reaction was vigorously stirred at 20 C for 67 h.
The autoclave was vented off, flushed with nitrogen and the
reaction mixture was directly analyzed by 1H NMR to
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determine the conversion of the olefin into the product. The
crude was then dried under reduced pressure and filtered off a
plug of silica gel eluting with CH2Cl2/Et2O 1:1 and finally the
solution was dried up in vacuum. The product was eventually
obtained after column chromatography on silica gel.
13C NMR (101 MHz, CDCl3) δ 170.4, 169.2, 168.0, 69.6, 68.7,
52.8, 48.1, 33.6, 21.9 (2C), 21.7, 21.6. ESI-MS: m/z=261 [M
+H]+; m/z=283 [M+Na]+; m/z=299 [M+K]+.
1,2-Dibenzyl 1-methyl ethane-1,1,2-tricarboxylate (3ab):
Synthesized following the general procedure and using BnOH
as nucleophile. The compound 3ab has been purified by
column chromatography petroleum ether/CH2Cl2 50:50 then
20:80, obtaining a colorless oil; isolated yield: 88% (0.627 g).
1H NMR (400 MHz, CDCl3) δ 7.40–7.29 (m, 10H), 5.20 (d, J=
12.3 Hz, 1H), 5.15 (d, J=12.3 Hz, 1H), 5.11 (s, 2H), 3.93 (t,
J=7.4 Hz, 1H), 3.70 (s, 3H), 3.01 (d, J=7.4 Hz, 2H). 13C
NMR (101 MHz, CDCl3) δ 170.6, 168.8, 168.2, 135.5, 135.3,
128.7 (2C), 128.54, 128.50, 128.4, 128.3, 67.6, 67.0, 52.9, 47.8,
33.3. ESI-MS: m/z=379 [M+Na]+; m/z=395 [M+K]+.
1-Benzyl 1,2-dimethyl ethane-1,1,2-tricarboxylate (3b): Syn-
thesized following the general procedure, the compound 3b has
been purified by column chromatography using petroleum
ether/CH2Cl2 50:50 then 30:70, obtaining a colorless oil;
1
isolated yield: 91% (0.510 g). H NMR (400 MHz, CDCl3) δ
7.40–7.29 (m, 5H), 5.22 (d, J=12.3 Hz, 1H), 5.17 (d, J=
12.3 Hz, 1H), 3.91 (t, J=7.4 Hz, 1H), 3.72 (s, 3H), 3.66 (s,
3H), 2.95 (d, J=7.4 Hz, 2H). 13C NMR (101 MHz, CDCl3) δ
171.3, 168.8, 168.2, 135.3, 128.7, 128.5, 128.2, 67.6, 53.0,
52.2, 47.8, 33.0. ESI-MS: m/z=281 [M+H]+; m/z=303 [M+
Na]+; m/z=319 [M+K]+.
Dimethyl 2-carbamoylsuccinate (5a): Synthesized following
the general procedure, but adding the solid olefin 4a directly
into the autoclave together with p-benzoquinone and p-TSA and
without filtering on a plug of silica gel. The compound 5a has
been purified by column chromatography petroleum ether/ethyl
acetate 50:50 then 30:70, obtaining a white powder; isolated
1,2-Dimethyl 1-phenyl ethane-1,1,2-tricarboxylate (3c): Fol-
lowing the general procedure, the olefin 2c was converted for
94%. The compound 3c has been purified by column
chromatography petroleum ether/CH2Cl2 20:80, obtaining a pale
1
1
yellow oil; isolated yield: 90% (0.479 g). H NMR (400 MHz,
yield: 91% (0.344 g). H NMR (400 MHz, CDCl3) δ 6.57 (bs,
CDCl3) δ 7.42–7.34 (m, 1H), 7.28–7.22 (m, 1H), 7.14–7.09 (m,
1H), 4.10 (dd, J=7.8, 7.0 Hz, 1H), 3.83 (s, 1H), 3.74 (s, 1H),
3.10 (dd, J=17.4, 7.9 Hz, 1H), 3.04 (dd, J=17.4, 6.9 Hz, 1H).
13C NMR (101 MHz, CDCl3) δ 171.3, 168.6, 167.2, 150.6,
129.6, 126.4, 121.4, 53.2, 52.4, 47.9, 33.1. ESI-MS: m/z=267
[M+H]+; m/z=289 [M+Na]+; m/z=305 [M+K]+.
1H), 5.77 (bs, 1H), 3.77 (s, 3H), 3.74 (t, J=6.8 Hz, 1H), 3.69
(s, 3H), 3.00 (d, J=6.8 Hz, 2H). 13C NMR (101 MHz, CDCl3) δ
172.2, 170.1, 169.0, 53.1, 52.2, 47.8, 32.5. ESI-MS: m/z=190
[M+H]+; m/z=212 [M+Na]+; m/z=228 [M+K]+.
Dimethyl 2-(isopropylcarbamoyl)succinate (5b): Synthesized
following the general procedure, but adding the solid olefin 4b
directly into the autoclave together with p-benzoquinone and p-
TSA. The compound 5b has been purified by column
chromatography petroleum ether/ethyl acetate 30:70, obtaining
a white powder; isolated yield: 92% (0.428 g). 1H NMR
(400 MHz, CDCl3) δ 6.24 (bs, 1H), 4.05 (m, 1H), 3.75 (s, 3H),
3.69 (s, 3H), 3.62 (t, J=6.9 Hz, 1H), 2.98 (d, J=6.9 Hz, 2H),
1.16 (d, J=6.6 Hz, 2H), 1.15 (d, J=6.5 Hz, 2H). 13C NMR
(101 MHz, CDCl3) δ 172.3, 170.5, 165.7, 52.9, 52.1, 48.4, 42.1,
32.7, 22.64, 22.59. ESI-MS: m/z=232 [M+H]+; m/z=254
[M+Na]+; m/z=270 [M+K]+.
1,2-Dimethyl 1-octadecyl ethane-1,1,2-tricarboxylate (3d):
Synthesized following the general procedure, but adding the
solid olefin 2d directly into the autoclave together with p-
benzoquinone and p-TSA. The compound 3d has been purified
by column chromatography petroleum ether/CH2Cl2 50:50 then
20:80, obtaining a white powder; isolated yield: 92% (0.814 g).
1H NMR (400 MHz, CDCl3) δ 4.21–4.08 (m, 2H), 3.85 (t, J=
7.4 Hz, 1H), 3.76 (s, 3H), 3.70 (s, 3H), 2.94 (d, J=7.4 Hz, 2H),
1.68–1.58 (m, 2H), 1.36–1.18 (m, 30H), 0.87 (t, J=6.7 Hz,
3H). 13C NMR (101 MHz, CDCl3) δ 171.4, 169.1, 168.5, 66.2,
52.9, 52.2, 47.8, 33.1, 32.1, 29.8 (8C), 29.72, 29.67, 29.5, 29.3,
28.6, 25.9, 22.8, 14.3. ESI-MS: m/z=443 [M+H]+; m/z=465
[M+Na]+; m/z=481 [M+K]+.
Dimethyl 2-(tert-butylcarbamoyl)succinate (5d): Following
the general procedure, but adding the solid olefin 4d directly
into the autoclave together with p-benzoquinone and p-TSA, a
conversion of 85% has been achieved. The compound 5d has
been purified by column chromatography petroleum ether/
CH2Cl2 50:50 then 30:70, obtaining a white powder; isolated
1-(Tert-butyl) 1,2-Dimethyl ethane-1,1,2-tricarboxylate (3e):
Following the general procedure, but using 5 mol% of catalyst
loading, olefin 2e was converted for 97%. The compound 3e
has been purified by column chromatography petroleum ether/
CH2Cl2 30:70, obtaining a colorless oil; isolated yield: 93%
1
yield: 78% (0.383 g). H NMR (400 MHz, CDCl3) δ 6.23 (bs,
1H), 3.75 (s, 3H), 3.68 (s, 3H), 3.58 (t, J=6.9 Hz, 1H), 2.95 (d,
J=6.9 Hz, 2H), 1.34 (s, 9H). 13C NMR (101 MHz, CDCl3) δ
172.4, 170.6, 165.6, 52.9, 52.1, 51.8, 49.0, 32.6, 28.7. ESI-MS:
m/z=246 [M+H]+; m/z=268 [M+Na]+; m/z=284 [M+
K]+.
1
(0.460 g). H NMR (400 MHz, CDCl3) δ 3.76 (t, J=7.4 Hz,
1H), 3.75 (s, 3H), 3.69 (s, 3H), 2.89 (d, J=7.4 Hz, 2H), 1.45 (s,
9H). 13C NMR (101 MHz, CDCl3) δ 171.6, 169.5, 167.4, 82.6,
52.8, 52.2, 48.8, 33.1, 28.0. ESI-MS: m/z=269 [M+Na]+;
m/z=285 [M+K]+.
Dimethyl 2-((2-hydroxyethyl)carbamoyl)succinate (5e): Syn-
thesized following the general procedure, without filtering on a
plug of silica gel. The compound 5e has been purified by
column chromatography petroleum ether/ethyl acetate 20:80,
1,2-Diisopropyl 1-methyl ethane-1,1,2-tricarboxylate (3aa):
Following the general procedure, but using 5 mol% of catalyst
i
loading and PrOH as nucleophile, olefin 2a was converted for
1
40%. The compound 3aa has been purified by column
obtaining a pale yellow oil; isolated yield: 98% (0.457 g). H
chromatography petroleum ether/CH2Cl2 50:50 then 30:70,
obtaining a yellow oil; isolated yield: 32% (0.166 g). H NMR
(400 MHz, CDCl3) δ 5.12–4.94 (m, 2H), 3.80 (t, J=7.5 Hz,
1H), 3.75 (s, 3H), 2.88 (d, J=7.5 Hz, 2H), 1.27–1.18 (m, 12H).
NMR (400 MHz, CDCl3) δ 7.05 (bs, 1H), 3.75 (s, 3H), 3.72–
3.66 (m, 3H), 3.68 (s, 3H), 3.50–3.35 (m, 2H), 3.00 (d, J=
6.9 Hz, 2H). 13C NMR (101 MHz, CDCl3) δ 172.4, 170.2,
1
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167.9, 61.8, 53.1, 52.3, 48.1, 42.8, 32.7. ESI-MS: m/z=234 [M
+H]+; m/z=256 [M+Na]+; m/z=272 [M+K]+.
82.2, 81.0, 45.9, 37.8, 36.2, 34.8, 28.2, 28.0. ESI-MS: m/z=
302 [M+H]+; m/z=324 [M+Na]+; m/z=340 [M+K]+.
Dimethyl 2-(morpholine-4-carbonyl)succinate (5f): Synthe-
sized following the general procedure, the compound 5f has
been purified by column chromatography petroleum ether/ethyl
acetate 50:50 then 40:60, obtaining a yellow oil; isolated yield:
Acknowledgements
This work was supported by MIUR, University of Bologna and
University of Urbino “Carlo Bo”. We are grateful to the
Department of Biomolecular Sciences of the University of
Urbino for providing NMR instrumentation.
1
98% (0.508 g). H NMR (400 MHz, CDCl3) δ 4.12 (dd, J=8.3,
5.8 Hz, 1H), 3.74 (s, 3H), 3.69 (s, 3H), 3.80–3.52 (m, 8H), 3.08
(dd, J=17.5, 8.4 Hz, 1H), 2.97 (dd, J=17.5, 5.8 Hz, 1H). 13C
NMR (101 MHz, CDCl3) δ 172.2, 169.1, 166.3, 66.8, 66.6,
53.0, 52.2, 46.9, 44.1, 43.0, 33.3. ESI-MS: m/z=260 [M+H]+;
m/z=282 [M+Na]+; m/z=298 [M+K]+.
References
Dimethyl 2-(dimethylcarbamoyl)succinate (5g): Synthesized
following the general procedure, the compound 5g has been
purified by column chromatography petroleum ether/ethyl
acetate 70:30 then 50:50, obtaining a yellow oil; isolated yield:
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95% (0.414 g). H NMR (400 MHz, CDCl3) δ 4.16 (dd, J=8.3,
5.9 Hz, 1H), 3.73 (s, 3H), 3.68 (s, 3H), 3.17 (s, 3H), 3.05 (dd,
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1H). 13C NMR (101 MHz, CDCl3) δ 172.2, 169.4, 167.8, 52.8,
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purified by column chromatography petroleum ether/ethyl
acetate 70:30 then 50:50, obtaining a yellow oil; isolated yield:
1
88% (0.481 g). H NMR (400 MHz, CDCl3) δ 5.01 (hept, J=
6.3 Hz, 1H), 4.97 (hept, J=6.3 Hz, 1H), 4.08 (dd, J=8.3,
5.9 Hz, 1H), 3.15 (s, 3H), 2.98 (dd, J=17.3, 8.4 Hz, 1H), 2.98
(s, 3H), 2.88 (dd, J=17.4, 5.9 Hz, 1H), 1.24 (d, J=6.3 Hz,
3H), 1.21 (d, J=6.3 Hz, 9H). 13C NMR (101 MHz, CDCl3) δ
171.4, 168.5, 168.0, 69.4, 68.4, 45.0, 37.9, 36.2, 34.0, 21.9
(2C), 21.8, 21.7. ESI-MS: m/z=274 [M+H]+; m/z=296 [M+
Na]+; m/z=312 [M+K]+.
Dibenzyl 2-(dimethylcarbamoyl)succinate (5gb): Synthesized
following the general procedure and using BnOH as nucleo-
phile. The compound 5gb has been purified by column
chromatography petroleum ether/CH2Cl2 50:50 then 20:80,
1
obtaining a yellow oil; isolated yield: 93% (0.686 g). H NMR
(400 MHz, CDCl3) δ 7.39–7.27 (m, 10H), 5.18–5.03 (m, 4H),
4.19 (dd, J=8.6, 5.7 Hz, 1H), 3.15 (dd, J=17.5, 8.6 Hz, 1H),
3.06 (s, 3H), 3.01 (dd, J=17.5, 5.7 Hz, 1H), 2.96 (s, 3H). 13C
NMR (101 MHz, CDCl3) δ 171.5, 168.7, 167.6, 135.7, 135.4,
128.71, 128.67, 128.5, 128.4, 128.3, 128.2, 67.4, 66.9, 44.7,
37.8, 36.2, 33.7. ESI-MS: m/z=370 [M+H]+; m/z=392 [M+
Na]+; m/z=408 [M+K]+.
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°
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Bis-Alkoxycarbonylation of Acrylic Esters and Amides for
the Synthesis of 2-Alkoxycarbonyl or 2-Carbamoyl Succi-
nates
Adv. Synth. Catal. 2019, 361, 1–13
D. Olivieri, R. Tarroni, N. Della Ca’, R. Mancuso, B.
Gabriele, G. Spadoni, C. Carfagna*