Diastereospecific Bis-alkoxycarbonylation of 1,2-Disubstituted Olefins Catalyzed by Aryl α-Diimine Palladium(II) Catalysts

Article abstract of DOI:10.1002/adsc.201701597

Readily synthesized aryl α-diimine derivatives have been used as efficient ligands for the palladium-catalyzed oxidative bis-alkoxycarbonylation reaction of 1,2-disubstituted olefins. The most active catalyst A was formed in situ from bis-(2,6-dimethylphenyl)-2,3-dimethyl-1,4-diazabutadiene and Pd(TFA)₂ (TFA=trifluoroacetate). This catalytic system was able to selectively convert 1,2-disubstituted olefins into 2,3-disubstituted-succinic diesters with total diastereospecificity, in good yields (up to 97%) with 2 mol% of catalyst loading, under mild reaction conditions (4 bar of CO at 20 °C in presence of p- toluenesulfonic acid as additive and p-benzoquinone as oxidant). The optimized reaction conditions could be successfully applied to 1,2-disubstituted aromatic, aliphatic, cyclic olefins and to unsaturated fatty acid methyl esters, employing methanol or benzyl alcohol as nucleophiles. The use of the bulky, less reactive isopropyl alcohol has allowed to better understand the mechanisms involved in the catalytic process. The geometry of the carbonylated products can be explained as a consequence of a concerted syn addition of the Pd-alkoxycarbonyl moiety to the olefin C=C bond. Catalyst A was isolated, characterized and analyzed by single crystal X-ray diffraction analysis. (Figure presented.).

Full text of DOI:10.1002/adsc.201701597

Title: Diastereospecific Bis-Alkoxycarbonylation of 1,2-disubstituted
Olefins Catalyzed by Aryl α-Diimine Palladium(II) Catalysts
Authors: Diego Olivieri, Francesco Fini, Rita Mazzoni, Stefano
Zacchini, Nicola Della Ca', Gilberto Spadoni, Bartolo Gabriele,
Raffaella Mancuso, Valerio Zanotti, and Carla Carfagna
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.201701597
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10.1002/adsc.201701597
Advanced Synthesis & Catalysis
FULL PAPER
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Diastereospecific Bis-alkoxycarbonylation of 1,2-Disubstituted
Olefins Catalyzed by Aryl α-Diimine Palladium(II) Catalysts
Diego Olivieri,a Francesco Fini,b* Rita Mazzoni,a Stefano Zacchini,a Nicola Della Ca’,c
Gilberto Spadoni,d Bartolo Gabriele,e Raffaella Mancuso,e Valerio Zanottia 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 Life Sciences, University of Modena and Reggio Emilia, Via G. Campi 103, 41125 Modena (MO), Italy
b
E-mail: francesco.fini@unimore.it
Department of Chemistry, Life Sciences and Environmental Sustainability (SCVSA), University of Parma, Parco Area
c
delle Scienze 17 A, 43124 Parma (Italy)
Department of Biomolecular Sciences, University of Urbino “Carlo Bo”, Piazza Rinascimento 6, 61029 Urbino (PU),
d
Italy
e
Department of Chemistry and Chemical Technologies, University of Calabria, Via P. Bucci 12/C, 87036 Arcavacata di
Rende (CS), Italy
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
Abstract. Readily synthesized aryl α-diimine derivatives successfully applied to 1,2-disubstituted aromatic, aliphatic,
have been used as efficient ligands for the palladium- cyclic olefins and to unsaturated fatty acid methyl esters,
catalyzed oxidative bis-alkoxycarbonylation reaction of 1,2- employing methanol or benzyl alcohol as nucleophiles. The
disubstituted olefins. The most active catalyst A was formed use of the bulky, less reactive isopropyl alcohol has allowed
in situ from bis-(2,6-dimethylphenyl)-2,3-dimethyl-1,4- to better understand the mechanisms involved in the
diazabutadiene and Pd(TFA)2 (TFA = trifluoroacetate). This catalytic process. The geometry of the carbonylated
catalytic system was able to selectively convert 1,2- products can be explained as a consequence of a concerted
disubstituted olefins into 2,3-disubstituted-succinic diesters syn addition of the Pd-alkoxycarbonyl moiety to the olefin
with total diastereospecificity, in good yields (up to 97%) C=C bond. Catalyst A was isolated, characterized and
with 2 mol% of catalyst loading, under mild reaction analyzed by single crystal X-ray diffraction analysis.
conditions (4 bar of CO at 20 °C in presence of p-
toluenesulfonic acid as additive and p-benzoquinone as Keywords: alkenes; aryl -diimine ligands; palladium;
oxidant). The optimized reaction conditions could be carbonylation; oxidative carbonylation; succinic acid esters
medicinal chemistry. In particular the succinic acid
Introduction
moiety is ubiquitous in molecules that act as
inhibitors of renin[5] and matrix metalloproteinases.[6]
Moreover succinates are employed in various
industrial fields, for instance in cosmetics,[7]
agricultural chemistry and in material science, where
they are largely used as non-phthalate plasticizers[8]
and as monomers for polymers and dendrimers.[9]
In literature various types of Pd-catalyzed olefin
bis-alkoxycarbonylations have been described using
phosphine or nitrogen ligands and molecular oxygen
or benzoquinone as oxidant.[3a,f] In particular,
stereoselective bis-alkoxycarbonylation reactions
have been widely studied,[10] but only very few
examples regarding disubstituted olefins have been
reported so far,[11] probably due to their lower
reactivity compared to α-olefins.[12] Recently, we
have reported a novel catalytic system able to
promote the alkoxycarbonylation of olefins and
Carbonylation reactions are among the most
important reactions in organic and organometallic
chemistry. They convert inexpensive feedstock such
as olefins and carbon monoxide into highly valuable
building blocks like aldehydes, esters or lactones.[1]
Despite the toxicity, carbon monoxide is one of the
preferred C1 building blocks especially in
combination with palladium catalysis. After the
pioneering contributions made by Heck and Tsuji,[2]
carbonylations are performed in the presence of an
oxidant to make the reaction conditions milder.[3]
Among
carbonylation
reactions,
the
bis-
alkoxycarbonylation is one of the most useful,
actually an olefin, carbon monoxide and a suitable
alcohol are converted into succinic acid derivatives,[4]
very important building blocks in organic and
1
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10.1002/adsc.201701597
Advanced Synthesis & Catalysis
alkynes.[13] The catalytic systems are made of a
palladium salt with 1,4-diaryl-2,3-diazabutadiene
With optimized experimental reaction conditions in
hand, we then proceeded to evaluate the scope of the
reaction.
(Ar2DABMe2)
or
bis(aryl)acenaphthenequinonediimine (diaryl-BIAN)
ligands. Analogous Pd(II) catalysts bearing aryl α-
diimine ligands were also used by us in the
copolymerization of styrenes with CO to yield
copolymers with a high degree of tacticity.[14] On the
basis of the acquired knowledge[13,14,15] and
considering the results obtained on the carbonylation
of terminal olefins,[13a] in this paper we have
extensively studied the diastereoselective bis-
alkoxycarbonylation reaction of 1,2-disubstituted
olefins with different alcohols for the synthesis of
2,3-disubstituted succinic acid esters, under mild
reaction conditions.
Table 1. Optimization of bis-methoxycarbonylation
reaction of cis--methylstyrene 2a.
N
N
N
N
1b
1a
MeO
N
N
OMe
1c
Results and Discussion
[Pd], 1a–1c, BQ 1.5 equiv.,
PCO= 4 bar, p-TSA 2 mol%,
MeOH/THF 7:1 (0.5 M),
20°C, 66h
COOMe
COOMe
As a disubstituted olefin benchmark, cis--
methylstyrene was used to optimize the reaction
conditions. Taking into account the conditions
previously employed in the case of terminal
olefins,[13a] a further optimization study on the ligands
and palladium sources in the oxidative bis-
alkoxycarbonylation reaction was performed. In the
initial experiment, the in situ formed complex
Pd(TFA)2/1a, in 0.5 mol% of catalyst loading, was
used with p-benzoquinone as oxidizing agent, p-
toluenesulfonic acid (p-TSA) as additive, in 7:1
MeOH/THF (0.5 M) as reaction medium, at 4 bar of
pressure of CO and room temperature, converting
only 50% of cis--methylstyrene (Table 1, entry 1).
By switching the ligand to the more straightforward
synthesized ligand 1b, the same result was obtained
in terms of conversion (50%, entry 2). Lowering the
2a
3a
Ligands
1a–1c
Conversion
(%)b)
Entrya)
[Pd]
Pd(TFA)2
0.5 mol%
Pd(TFA)2
0.5 mol%
Pd(TFA)2
0.1 mol%
Pd(TFA)2
0.01 mol%
Pd(TFA)2
0.5 mol%
Pd(OAc)2
0.5 mol%
(PhCN)2PdCl2
0.5 mol%
Pd(TFA)2
2 mol%
1a
0.55 mol%
1b
1
2
50
50
0.55 mol%
1b
3
21
0.11 mol%
1b
0.011 mol%
4
<5
1c
5
<5
0.55 mol%
1b
0.55 mol%
concentration of the catalyst Pd(TFA)2/1b
a
6
25
detrimental effect on the conversion has been
detected (table 1, entries 3 and 4). On the other hand,
by using ligand 1c no conversion was observed,
confirming the necessity for an ortho-disubstituted
diaryl α-diimine ligand (table 1, entry 5).[13]
1b
7c)
8
35
0.55 mol%
1a
2.2 mol%
≥98
≥98
Besides ligands, other palladium sources were tested
in order to improve the efficiency of the process.
Pd(TFA)2
2 mol%
1b
2.2 mol%
9
However,
neither
Pd(OAc)2
nor
a) Reaction performed in autoclave at PCO = 4 bar, with cis-
-methylstyrene 2a (2 mmol-scale), palladium salts [Pd]
(0.01 - 2 mol%), ligands 1a–c (0.011 - 2.2 mol%), 2 mol%
of p-TSA and 1.5 equiv. of BQ, in 7:1 MeOH/THF (0.5M)
(PhCN)2PdCl2/2AgOTf were active enough to raise
the conversion of the carbonylation reaction (Table 1,
entries 6 and 7). Complete substrate conversion was
instead observed when increasing the catalyst loading
up to 2 mol% with both ligands 1a and 1b (entries 8
and 9). Due to its easier synthesis, the ligand of
choice for the next experiments was 1b (see
Experimental Section). Thus, the combination of
Pd(TFA)2/1b (2 mol%) with benzoquinone as the
oxidizing agent, p-TSA (2 mol%) as the acidic
additive and 7:1 MeOH/THF (0.5 M) solution as
reaction medium allowed obtaining the syn-2,3-
disubstituted succinic acid methyl ester 3a with total
diastereospecificity under particularly mild reaction
conditions, such as room temperature 20 °C and 4 bar
of CO (Table 1, entry 9).
b)
as the reaction medium, for 66 h. Determined by direct
1H NMR analysis on a sample of the reaction mixture.
c)
Reaction performed by using 1.2 mol% of AgOTf instead
of p-TSA.
Several 1,2-disubstituted aromatic, aliphatic and
cyclic olefins were used together with different
alcohols as nucleophiles (Table 2). In general,
moderate to excellent results were achieved in the
bis-alkoxycarbonylation of internal olefins. 2,3-
Disubstituted aromatic and aliphatic methyl
succinates 3a, 3d, 3g, 3j, 3m (Table 2, entries 1, 4, 7,
2
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10.1002/adsc.201701597
Advanced Synthesis & Catalysis
Table 2. (Continued)
10, 13) and benzyl esters 3b, 3e, 3h, 3k, 3n (entries 2,
5, 8, 11, 14) were obtained with excellent isolated
yields, up to 97%, and a total diastereospecificity.
In particular, all reactions performed with the
optimized reaction conditions and methanol or benzyl
alcohol as nucleophiles, gave complete conversion of
the starting olefins, and near quantitative isolated
yields of the corresponding products even with the
cyclic olefin 2c (Table 2, entries 7–8). Interestingly
1,2-dialkyl substituted olefins (2d, 2e) gave similar
results to those obtained with the aromatic ones and,
at the best of our knowledge, this is the first time that
the bis-alkoxycarbonylation was successfully applied
to such alkenes (entries 10–11, 13–14).
With less nucleophilic isopropyl alcohol, less
satisfactory results were attained. In particular,
although the aromatic -methylstyrenes 2a and 2b
were fully converted, only 40% and 50% isolated
yields of the corresponding succinic esters 3c and 3f
were achieved (Table 2 entries 3 and 6).
Table 2. Scope of the bis-alkoxycarbonylation of aromatic
and aliphatic 1,2-disubstituted olefins 2a–2e.
[a]
Reactions performed in autoclave at PCO of 4 bar, with
olefins 2a–2e (2 mmol-scale), 2 mol% of Pd(TFA)2, 2.2
mol% of 1b, 2 mol% of p-TSA and 1.5 equiv. of BQ, in
7:1 R3OH/THF (0.5M) as the reaction medium, for 66 h. [b]
[c]
Isolated yields after column chromatography.
Conversion of the 1,2-disubstituted olefins and, in
parenthesis, isolated yields of the converted products are
reported.
In both cases, together with 3c and 3f, the respective
byproducts 4a and 4b were formed, deriving from the
ability of hydroquinone (generated by reduction of
benzoquinone under the reaction conditions) to act as
a nucleophile, thus competing with the isopropanol
(Scheme 1).
3
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10.1002/adsc.201701597
Advanced Synthesis & Catalysis
methyl oleate 2i a 50% of conversion was observed
(table 3, entry 4).18
Table 3. Bis-methoxycarbonylation of aliphatic 1,2-
disubstituted olefins 2f–2j.
Scheme 1. Formation of by-products 4a and 4b
By-products 4a and 4b have been isolated (4a Y. =
46 %, 4b Y. = 41 %)[16] and fully characterized.
To identify the structures of compounds 4a and b, in
1
addition to H and 13C NMR spectra (Figure S8 and
Figure S11), it was necessary to perform HMBC
experiments that allowed us to find out that, in both
cases, the isopropoxy carbonyl group is bound to the
CH bearing the methyl (Figure S9). This carbon-bond
connectivity was also confirmed by XRD analysis of
single crystals of 4b obtained upon slow diffusion of
n-hexane into a dichloromethane solution of the
compound (Figure S10 and Table S4). Although
compounds 4a, 4b represent the by-products of the
carbonylation reactions of olefins 2a and 2b with i-
PrOH, they can be regarded as interesting products as
they contain two different ester moieties that may
have a diverse reactivity in further reactions.
Moreover, the identification of structure of
compounds 4a and 4b provided further details on the
catalytic cycle of the bis-alkoxycarbonylation process
(vide infra). The carbonylation reactions of aliphatic
1,2-disubstituted olefins 2c, 2d and 2e with isopropyl
alcohol did not give analogous results compared with
the aromatic olefins. Although esters 3i, 3l and 3o
were isolated stereospecifically, conversions and
yields were less satisfactory, even after further
reaction optimization (Table 2, entries 9, 12 and
15).[17]
Considering the excellent results obtained in the
bis-methoxycarbonylation of the aliphatic olefins 2d
and 2e (table 2, entries 10 and 13), in order to
evaluate how general this reaction is, alkenes with a
double bond remote from the terminal methyl group,
such as trans-3-octene 2f, cis-4-octene 2g and trans-
4-octene 2h, were also tested. Complete conversions
of the trans olefins 2f and 2h have been achieved,
obtaining the corresponding carbonylated products 3p
and 3r with 92% and 76% isolated yields respectively
(table 3, entry 1 and entry 3). Even if only 49% of
cis-4-octene has been transformed in the carbonylated
compound 3q, almost all the product was recovered
(table 3, entry 2). Finally, olefins containing a more
internal double bond, such as unsaturated fatty acid
methyl esters, were tested as substrates. While the
methyl trans-9-octadecenoate 2j has been fully
converted, obtaining the bis-carbonylated product 3t
in 78% isolated yield (table 3, entry 5), with the
[a]
Reactions performed in autoclave at PCO of 4 bar, with
olefins 2f–2j (2 mmol-scale), 2 mol% of Pd(TFA)2, 2.2
mol% of 1b, 2 mol% of p-TSA and 1.5 equiv. of BQ, in
7:1 MeOH/THF (0.5M) as the reaction medium, for 66 h.
[b]
[c]
Isolated yields after column chromatography.
[d]
Conversion of the 1,2-disubstituted olefins.
yield of product relative to the olefin conversion.
Reaction time 96 h.
Isolated
[e]
All the products 3p-3t were obtained with a total
diastereospecificity and the trans aliphatic alkenes
appear to be more reactive than the cis ones. This is
the first time that the bis-alkoxycarbonylation of
unsaturated fatty acid methyl esters, without
isomerization of the double bond, yielding to methyl
tricarboxylate compounds, is reported. Indeed, in
literature, alkoxycarbonylations of internal olefins,
such as 3-octene and 4-octene,[19] and of unsaturated
fatty acids or fatty acid methyl esters,[20] lead to linear
esters and to linear α,ω dicarboxylic acid diesters
respectively, through a Pd-catalyzed isomerizing
methoxycarbonylation process.
4
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10.1002/adsc.201701597
Advanced Synthesis & Catalysis
Keeping in mind the above results and the
literature data,[4k,13,14,21,22] the catalytic cycle depicted
in Scheme 2 is proposed, summarizing all the
reactions involved in the bis-alkoxycarbonylation
process. The (bis(2,6-dimethylphenyl)butane-2,3-
diimine) palladium(II)bis(trifluoroacetate) catalyst A
(Scheme 2, top) is formed in situ from the reaction
between Pd(TFA)2 and the ligand 1b in THF.
With the intent of isolating and characterizing the
catalyst, A was ad hoc synthesized, as reported in the
Experimental Section. Because of the insolubility of
A in the most common solvents and its degradation in
DMSO, the NMR spectra were recorded in CDCl3,
Figure 1. Complex A
after dissolving
A
in few microliters of
hexafluoroisopropanol (HFIP).
1
The observed behaviour confirms the formation of
the palladium complex and it is in agreement with the
electron withdrawing effect of the metal center.
From the H NMR spectrum it appears that the
signals of the protons H4, H5 and H7 of the complex
A (Figure 1) are shifted downfield (about 0.10 - 0.30
ppm) respect to the free ligand 1b, while the signal of
H3 remains constant (Table S1, Supporting
Information).
Analogous
complexes
with
bipyridine,
phenanthroline or aryl α-diimine ligands have been
previously reported.[23] Red/orange single crystals of
A·(CF3)2CHOH, suitable for XRD analysis, were
obtained by slow evaporation of the solvent, after
dissolving the catalyst in a small amount of HFIP and
adding CHCl3. Complex A (Figure 2 and Table S3)
displays the expected square-planar geometry, with
two coordination sites of the Pd(II) centre occupied
by the aryl α-diimine ligand and the other two sites
by two trifluoroacetate ligands. The bonding
parameters are similar to those previously found in
analogous complexes.[23c,24] The angles between the
planes of the two aromatic rings and the least-squares
plane comprising Pd(1), N(1), N(2), O(1) and O(3)
are 87.43(16)° and 83.68(15)°, respectively. Within
the unit cell of A·(CF3)2CHOH, a hydrogen bond is
present, involving the O(5)-H(5) group of the co-
crystallized HFIP molecule and O(2), which belongs
to one of the trifluoroacetate ligands of A [O(5)-H(5)
0.84 Å, H(5)···O(2) 1.91 Å, O(5)···O(2) 2.739(9) Å,
<O(5)H(5)O(2) 169.3°].
Figure 2. Molecular structure of Complex A.
Displacement ellipsoids are at the 30% probability level.
Hydrogen atoms have been omitted for clarity.
Scheme 2. Proposed catalytic cycle
Moreover, in the 13C NMR spectrum all the carbon
signals are shifted downfield (about 2.1 - 9.1 ppm)
compared to free ligand 1b, with the exception of the
aromatic carbon C1 directly linked to the nitrogen
atom that is shifted upfield (Table S2).
Taking up the description of the catalytic cycle,
reaction of A with the alcohol allows the formation of
the active species B and the insertion of CO leads to
the alkoxycarbonyl-palladium complex C (Scheme 2).
The successive coordination and insertion of the
5
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10.1002/adsc.201701597
Advanced Synthesis & Catalysis
alkene in C affords the 5-membered palladacycle D.
In the case of cis- or trans-β-methylstyrene, where R1
is a phenyl ring, the η3-allylic intermediate D’ could
be in equilibrium with D.[14, 25] In any case, further
CO insertion gives the complex E. Intermediates
similar to D,[22] D’[21] and E[21b] have been previously
isolated and characterized by us through
to isopropanol makes the first one more reactive, but
being the i-PrOH present in great excess, the
succinate esters 3 and the by-products 4 are formed in
almost equal quantities. Furthermore, from the
structure of 4a and 4b it can be deduced that, while in
the highly hindered intermediate E there is a
competition between the two nucleophiles, in the
intermediate F only the i-PrOH, present in greater
amounts, reacts regenerating the active species B
(Scheme S1, Supporting Information). This
information on the catalytic cycle could be useful to
design the synthesis of succinates with two different
ester functionalities.
stoichiometric
model
reactions.
Finally,
a
nucleophilic attack of the alcohol on the carbonyl
linked to Pd in the intermediate E, leads to the final
product 3 and the palladium hydride complex F.
Benzoquinone regenerates the active species B
closing the catalytic cycle (Scheme 2).[26]
The conservation of the trans or cis geometry of the
1-2 disubstituted alkene, in the palladacycle
intermediate D, can be explained through a concerted
syn addition of the Pd-alkoxycarbonyl moiety to the
olefin C=C bond (Scheme 3).[22a,27] The resulting
four-membered transition states TS-trans and TS-cis,
depicted in Scheme 3, account for the
diastereospecificity of the bis-alkoxycarbonylation
reaction.
DFT studies are underway to better understand all
steps of the catalytic cycle.
Conclusions
An efficient method for the Pd-catalyzed bis-
alkoxycarbonylation of 1,2-disubstituted olefins 2 to
give 2,3-disubstituted-succinic diesters 3 has been
developed, using Pd(TFA)2 as palladium source, bis-
(2,6-dimethylphenyl)-2,3-dimethyl-1,4-
diazabutadiene as ligand and p-benzoquinone as
oxidant. The process is diastereospecific, due to the
syn addition of the olefinic double bond to the
alkoxycarbonyl palladium intermediate C. Moreover
the high selectivity of the reaction and the nearly
quantitative yields with aromatic, cyclic and aliphatic
olefins using methanol or benzyl alcohol as
nucleophiles, under particularly mild reaction
conditions (4 bar of CO at 20°C), demonstrate the
high efficiency of our catalytic system. For the first
time the bis-alkoxycarbonylation reaction of 1,2-
dialkyl substituted olefins and of unsaturated fatty
acid methyl esters has been successfully realized,
obtaining
the
corresponding
products
stereospecifically, in good to excellent yields. In
particular, if one of the substituents on the double
bond is a methyl or an ethyl group the best results
were achieved (yields up to 96%), while with alkenes
bearing a more internal double bond, the results are
slightly less satisfactory and the trans olefins resulted
to be more reactive than the cis ones.
Interestingly, under our reaction conditions, olefin
isomerization is not observed, as often happens in Pd
catalyzed processes.[3f] In conclusion our bis-
alkoxycarbonylation reaction appears to be very
general since it can be applied to a large number of
different types of 1,2-disubstituted olefins.
The high reactivity of the catalytic system is probably
due to the conformation of the palladium
intermediates having the aryl rings of the ligand 1b
almost perpendicular to the Pd coordination plane,
because of the presence of substituents in the ortho
positions.[21] This conformation probably favours the
leaving of the succinate ester products 3, enhancing
the efficiency of the reactions. The structure of
palladium catalyst A has been fully identified by
NMR and XRD analysis. Based on the above results
and the organometallic palladium intermediates,
Scheme 3. Syn addition of the Pd-alkoxycarbonyl fragment
to the cis or trans olefins
The proposed catalytic cycle (Scheme 2) allows us to
figure out also the causes for the formation of by-
products 4, occurring in the reactions between β-
methylstyrenes and i-PrOH as nucleophile (Scheme
1). Considering the 2-1 regioselectivity of the
insertion of the β-methylstyrenes[22a] into the Pd-
alkoxycarbonyl bond of complex C (Scheme 2), the
formation of both compounds 3 and 4 may results
from
a competition between isopropanol and
hydroquinone (formed during the catalytic cycle) to
act as nucleophiles towards the intermediate E. The
smaller steric hindrance of hydroquinone compared
6
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10.1002/adsc.201701597
Advanced Synthesis & Catalysis
reaction was vigorously stirred at the room temperature
(20°C) for 66 h. The autoclave was vented off, flushed
with nitrogen and the reaction mixture was directly
previously isolated and characterized by us in model
reactions, a catalytic cycle, explaining the complete
diastereoselectivity of the process, has been proposed.
The use of the bulky isopropyl alcohol as nucleophile
has allowed us to draw some further conclusions
about the mechanism of the catalytic process.
1
analyzed by H NMR to determine the conversion of the
olefins 2. The crude was then dried under reduced pressure
and filtered off a plug of silica gel, washing with
CH2Cl2/Et2O 1:1 (150 mL) finally the solution was dried
up in vacuum. Then NaOH 1M (30 mL) was added and the
solution was extracted with CH2Cl2 (3 x 30 mL). The
combined organic solution was dried over Na2SO4 and the
solvent was removed under reduced pressure. The product
was eventually obtained after column chromatography on
silica gel (Petroleum ether/CH2Cl2 50:50 then 20:80; if
benzyl alcohol was used as nucleophiles: Petroleum
ether/CH2Cl2 70:30 then 50:50).
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.
(2R*,3R*)-Dibenzyl
(3b): Following the general procedure, compound 3b was
obtained as a white powder; yield: 92% (0.715 g). H
2-methyl-3-phenylsuccinate
1
Reactions were monitored by H NMR taking a direct
1
1
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  scale relative to residual CHCl3
NMR δ 7.47–7.27 (m, 13H), 7.14–7.07 (m, 2H), 5.22 (d, J
= 12.4 Hz, 1H), 5.13 (d, J = 12.4 Hz, 1H), 4.94 (s, 2H),
4.02 (d, J = 11.0 Hz, 1H), 3.46 (dq, J = 11.0, 6.8 Hz, 1H),
1.40 (d, J = 6.8 Hz, 3H). 13C NMR δ 173.8, 171.9, 136.5,
135.61, 135.56, 128.6, 128.5, 128.43, 128.37, 128.2, 128.0,
127.93, 127.91, 127.7, 66.6, 66.2, 54.9, 43.7, 16.4. ESI-
MS: m/z=389 [M+H]+.
(2R*,3R*)-Diisopropyl 2-methyl-3-phenylsuccinate
(3c): Following the general procedure, compound 3c was
obtained as a colorless oil; yield: 40% (0.232 g). H NMR
δ 7.37–7.31 (m, 2H), 7.30–7.19 (m, 3H), 4.99 (hept, J =
6.3 Hz, 1H), 4.72 (hept, J = 6.3 Hz, 1H), 3.71 (d, J = 11.2
Hz, 1H), 3.20 (dq, J = 11.2, 6.8 Hz, 1H), 1.28 (d, J = 6.8
Hz, 3H), 1.23 (d, J = 6.3 Hz, 3H), 1.13 (d, J = 6.3 Hz, 3H),
1.01 (d, J = 6.3 Hz, 3H), 0.83 (d, J = 6.2 Hz, 3H). 13C
NMR δ 173.9, 171.9, 137.1, 128.6, 128.5, 127.7, 68.5, 67.7,
55.6, 44.0, 21.9, 21.63, 21.59, 21.4, 16.5. ESI-MS:
m/z=293 [M+H]+.
1
(7.26 ppm) for H NMR and to the central line of CDCl3
(77.16 ppm) for 13C NMR. 13C NMR were recorded with
1H broadband decoupling. 19F NMR were recorder on a
Varian Mercury Plus VX 400 (19F: 376 MHz), using
CDCl3 as solvent. The following abbreviations were used
to explain the multiplicities: s = singlet, d = doublet, t =
triplet, q = quartet, hept = heptet, m = multiplet, dd =
double doublets, dq = double quartets, td = triple doublets.
Mass spectra were recorded on a LC-MS apparatus Agilent
Ion-Trap 6310A 2795, using electrospray (ES+ or ES-)
ionisation techniques. Carbon monoxide (Cp grade
99.99%) was supplied by Air Liquide, p-benzoquinone was
purchased by Sigma-Aldrich and was recrystallized from
n-heptane/EtOH mixture, olefins 2a–2j were purchased
from Sigma-Aldrich, Alfa Aesar or TCI, filtered off a plug
of neutral Al2O3 and used without further purification.
Anhydrous THF was distilled from sodium-benzophenone,
methanol was distilled from Mg(OMe)2 and isopropyl
alcohol was distilled from CaH2. Pd(TFA)2 was weighted
in an analytical balance without excluding moist and air.
All other chemicals were purchased from Sigma-Aldrich
and used without further purification. Ligand 1a was
synthesized by our group according to a previously
reported procedure.[14] Ligands 1b and 1c, used in the
optimization reaction, were synthesized according to
previously reported procedure.[28] Compounds 3a, 3d, 3g,
3i were already known and the spectral date are identical to
the previously reported literature data (see supporting
information for more details).[4c,13a, 29]
1
(2S*,3R*)-Dibenzyl
(3e): Following the general procedure, compound 3e was
obtained as a colorless oil; yield: 90% (0.699 g). H NMR
2-methyl-3-phenylsuccinate
1
δ 7.43–7.26 (m, 13H), 7.20–7.14 (m, 2H), 5.17 (d, J = 12.4
Hz, 1H), 5.12 (d, J = 12.4 Hz, 1H), 5.08 (d, J = 12.6 Hz,
1H), 5.03 (d, J = 12.6 Hz, 1H), 3.90 (d, J = 11.4 Hz, 1H),
3.30 (dq, J = 11.4, 7.3 Hz, 1H), 1.02 (d, J = 7.3 Hz, 3H).
13C NMR δ 175.4, 172.9, 136.3, 135.98, 135.89, 129.0,
128.62, 128.59, 128.4, 128.3, 128.2, 128.0, 127.9, 127.8,
66.60, 66.59, 54.5, 42.5, 15.5. ESI-MS: m/z=389 [M+H]+.
(2S*,3R*)-Diisopropyl 2-methyl-3-phenylsuccinate
(3f): Following the general procedure, compound 3f was
CCDC.1588018
(complex
A·(CF3)2CHOH
and
CCDC.1588019 (compound 4b) contain the supplementary
crystallographic data for this paper. These data can be
obtained free of charge from The Cambridge
Crystallographic
www.ccdc.cam.ac.uk/data_request/cif.
Data
Centre
via
1
obtained as a colorless oil; yield: 50% (0.292 g). H NMR
δ 7.35–7.24 (m, 5H), 5.03 (hept, J = 6.3 Hz, 1H), 4.94
(hept, J = 6.3 Hz, 1H), 3.69 (d, J = 11.4 Hz, 1H), 3.09 (dq,
J = 11.4, 7.3 Hz, 1H), 1.28 (d, J = 6.3 Hz, 3H), 1.24 (d, J =
6.3 Hz, 3H), 1.21 (d, J = 6.3 Hz, 3H), 1.05 (d, J = 6.2 Hz,
3H), 0.94 (d, J = 7.3 Hz, 3H). 13C NMR δ 175.3, 172.7,
136.9, 128.8, 128.5, 127.6, 68.3, 68.0, 54.7, 42.8, 21.9,
21.80, 21.76, 21.4, 15.6. ESI-MS: m/z=293 [M+H]+.
Typical procedure for the bis-alkoxycarbonylation
reaction of 1,2-disubstituted olefins.
In a nitrogen flushed Schlenk tube, equipped with a
magnetic stirring bar, the respective olefins 2a–j (2 mmol)
and the alcohol R3OH (3.5 mL) were added in sequence.
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) and THF
(0.5 mL) were added in sequence. After the mixture turned
in a red/brown color (20 min), the ligand 1b (12.8 mg,
0.044 mmol) was added. The mixture was left under
stirring for 10 min, turning in a dark orange color. The
olefin solution and the formed catalyst was injected in
sequence in a nitrogen flushed autoclave, equipped with a
magnetic stirring bar, containing benzoquinone (325 mg, 3
mmol) and p-TSA·H2O (7.6 mg, 0.04 mmol). After 10 min
of stirring, the autoclave was flushed three times with CO
and pressurized with 4 bar of carbon monoxide. The
(1R*,2S*)-Dibenzyl cyclohexane-1,2-dicarboxylate
(3h): Following the general procedure, compound 3h was
1
obtained as a colorless oil; yield: 80% (0.564 g). H NMR
δ 7.40–7.28 (m, 10H), 5.08 (d, J = 12.4 Hz, 2H), 5.03 (d, J
= 12.4 Hz, 2H), 2.95–2.88 (m, 2H), 2.12–2.01 (m, 2H),
1.86–1.75 (m, 2H), 1.59–1.35 (m, 4H). 13C NMR δ 173.5,
136.1, 128.5, 128.24, 128.17, 66.3, 42.7, 26.3, 23.8. ESI-
MS: m/z=353 [M+H]+.
7
This article is protected by copyright. All rights reserved.

10.1002/adsc.201701597
Advanced Synthesis & Catalysis
(2R*,3S*)-Dimethyl 2-methyl-3-pentylsuccinate (3j):
NMR δ 175.4, 175.1, 51.68, 51.67, 48.0, 46.2, 29.1, 28.9,
22.7, 22.2, 13.95, 11.3. ESI-MS: m/z=231 [M+H]+.
(2R*,3S*)-Dimethyl 2,3-dipropylsuccinate (3q):
Following the general procedure, compound 3j was
1
obtained as a pale yellow oil; yield: 92% (0.423 g). H
NMR δ 3.68 (s, 3H), 3.67 (s, 3H), 2.73–2.62 (m, 2H),
1.70–1.54 (m, 1H), 1.43–1.31 (m, 1H), 1.31–1.17 (m, 6H),
1.12 (d, J = 6.7 Hz, 3H), 0.85 (t, J = 6.8 Hz, 3H). 13C NMR
Following the general procedure, compound 3q was
obtained as a colorless oil; yield: 91% (0.205g) over a
conversion of 49% of cis-4-octene 2g, determined by H
1
δ 175.5, 174.8, 51.9, 51.7, 48.7, 42.2, 31.7, 30.8, 27.2, 22.5, NMR analysis on a direct sample of the reaction mixture.
15.3, 14.1. ESI-MS: m/z=231 [M+H]+.
(2R*,3S*)-Dibenzyl 2-methyl-3-pentylsuccinate (3k):
Following the general procedure, compound 3k was
1H NMR δ 3.69 (s, 6H), 2.70–2.59 (m, 2H), 1.67–1.51 (m,
2H), 1.37–1.17 (m, 6H), 0.87 (t, J = 7.1 Hz, 6H). 13C NMR
δ 175.1, 51.7, 48.4, 33.2, 20.8, 14.0. ESI-MS: m/z=231
[M+H]+.
1
obtained as a colorless oil; yield: 89% (0.681 g). H NMR
δ 7.39–7.28 (m, 10H), 5.14–5.05 (m, 4H), 2.81–2.69 (m,
2H), 1.69–1.55 (m, 1H), 1.41–1.30 (m, 1H), 1.26–1.15 (m,
6H), 1.13 (d, J = 6.6 Hz, 3H), 0.82 (t, J = 6.8 Hz, 3H). 13C
NMR δ 174.6, 174.0, 135.90, 135.88, 128.60, 128.58,
128.5, 128.34 (2C), 128.32, 66.5, 66.4, 48.7, 42.3, 31.5,
30.7, 27.1, 22.4, 15.1, 14.0. ESI-MS: m/z=383 [M+H]+.
(2S*,3S*)-Dimethyl
Following the general procedure, compound 3r was
obtained as a pale yellow oil; yield: 76% (0.350 g). H
NMR δ 3.65 (s, 6H), 2.72–2.63 (m, 2H), 1.63–1.48 (m,
4H), 1.36–1.16 (m, 4H), 0.89 (t, J = 7.3 Hz, 6H). 13C NMR
δ 175.3, 51.7, 46.6, 31.4, 20.3, 14.1. ESI-MS: m/z=231
[M+H]+.
2,3-dipropylsuccinate
(3r):
1
(2R*,3S*)-Diisopropyl
2-methyl-3-pentylsuccinate
(3l): Following the general procedure, olefin 2d were
converted for 42%, obtaining compound 3l as a pale
orange oil with 43% of yield (0.103 g) over the converted
(8R*,9S*)-Trimethyl
heptadecane-1,8,9-
tricarboxylate (3s): Following the general procedure,
compound 3s was obtained as a colorless oil after column
chromatography on silica gel (Petroleum ether/CH2Cl2
1
olefin. H NMR δ 5.10–4.96 (m, 2H), 2.67–2.56 (m, 2H),
1.69–1.57 (m, 1H), 1.44–1.34 (m, 1H), 1.34–1.18 (m, 18H), 30:70 then CH2Cl2, in this case the previous extraction
1.12 (d, J = 6.5 Hz, 3H), 0.86 (t, J = 6.4 Hz, 3H). 13C NMR
δ 174.6, 173.9, 67.9, 67.8, 48.9, 42.6, 31.7, 30.8, 27.1, 22.5,
22.0 (2C), 21.94, 21.88, 15.3, 14.1. ESI-MS: m/z=287
[M+H]+.
with NaOH 1M / CH2Cl2 was not carried out due to 3s
water solubility); yield: 92% (0.381g) over a conversion of
1
50% of methyl oleate 2i, determined by H NMR analysis
1
on a direct sample of the reaction mixture. H NMR δ 3.69
(2S*,3S*)-Dimethyl
(3m): Following the general procedure, compound 3m was
obtained as a pale yellow oil; yield: 96% (0.442 g). H
2-methyl-3-pentylsuccinate
(s, 6H), 3.66 (s, 3H), 2.67–2.57 (m, 2H), 2.29 (t, J = 7.5 Hz,
2H), 1.65–1.52 (m, 4H), 1.38–1.13 (m, 22H), 0.87 (t, J =
6.9 Hz, 3H). 13C NMR δ 175.0, 174.98, 174.4, 51.7 (2C),
51.5, 48.47, 48.45, 34.1, 31.9, 30.97, 30.91, 29.40, 29.39,
29.24, 29.19, 29.0 (2C), 27.40, 27.35, 24.9, 22.7, 14.2.
ESI-MS: m/z=415 [M+H]+.
1
NMR δ 3.66 (s, 3H), 3.65 (s, 3H), 2.78 (dq, J = 7.3, 8.3 Hz,
1H), 2.67 (dt, J = 4.4, 8.6 Hz, 1H), 1.64 – 1.46 (m, 2H),
1.34 – 1.18 (m, 6H), 1.16 (d, J = 7.1 Hz, 3H), 0.86 (t, J =
6.8 Hz, 3H). 13C NMR δ 175.8, 175.4, 51.9, 51.7, 47.5,
40.9, 31.8, 28.7, 26.6, 22.5, 14.3, 14.1. ESI-MS: m/z=231
[M+H]+.
(2S*,3S*)-Dibenzyl 2-methyl-3-pentylsuccinate (3n):
Following the general procedure, compound 3n was
obtained as a colorless oil; yield: 97% (0.742 g). H NMR
(8R*,9R*)-Trimethyl
heptadecane-1,8,9-
tricarboxylate (3t): Following the general procedure,
compound 3t was obtained as a pale yellow oil after
column chromatography on silica gel (Petroleum
ether/CH2Cl2 30:70 then CH2Cl2, in this case the previous
1
extraction with NaOH 1M / CH2Cl2 was not carried out
1
δ 7.40–7.27 (m, 10H), 5.13–4.99 (m, 4H), 2.89 (dq, J = 7.1, due to 3t water solubility); yield: 78% (0.647 g). H NMR
1.1 Hz, 1H), 2.78 (dt, J = 4.1, 8.7 Hz, 1H), 1.73–1.48 (m,
2H), 1.33–1.21 (m, 6H), 1.19 (d, J = 7.1 Hz, 3H), 0.85 (t, J
= 6.8 Hz, 3H). 13C NMR δ 175.1, 174.6, 136.1, 136.0,
128.60, 128.57, 128.4, 128.31, 128.27, 128.25, 66.5, 66.4,
47.5, 40.95, 31.8, 28.7, 26.6, 22.5, 14.3, 14.1. ESI-MS:
m/z=383 [M+H]+.
δ 3.66 (s, 9H), 2.72–2.61 (m, 2H), 2.29 (t, J = 7.5 Hz, 2H),
1.64–1.49 (m, 6H), 1.34–1.16 (m, 20H), 0.87 (t, J = 6.8 Hz,
3H). 13C NMR δ 175.38, 175.36, 174.4, 51.80, 51.79, 51.6,
46.82, 46.80, 34.2, 31.97, 29.7, 29.51, 29.47, 29.35, 29.28,
29.25, 29.17 (2C), 27.04, 27.01, 25.0, 22.8, 14.3. ESI-MS:
m/z=415 [M+H]+.
(2S*,3S*)-Diisopropyl
2-methyl-3-pentylsuccinate
(2R*,3R*)-1-(4-hydroxyphenyl)-4-methyl-3-methyl-
2-phenylsuccinate (4a): Following the general procedure,
compound 4a was obtained as a pale yellow oil after
column chromatography on silica gel (CH2Cl2 then
Et2O/CH2Cl2 5:95, in this case the previous extraction with
NaOH 1M / CH2Cl2 was not carried out due to 4a water
solubility); yield: 46% (0.315 g). 1H NMR δ 7.44–7.39 (m,
2H), 7.36–7.26 (m, 3H), 6.85–6.71 (m, 4H), 4.77 (hept, J =
6.3 Hz, 1H), 4.00 (d, J = 10.9 Hz, 1H), 3.30 (dq, J = 6.8,
10.9 Hz, 1H), 1.39 (d, J = 6.8 Hz, 3H), 1.05 (d, J = 6.3 Hz,
3H), 0.86 (d, J = 6.2 Hz, 3H). 13C NMR δ 174.2, 171.9,
154.1, 143.6, 136.1, 128.8, 128.6, 128.1, 122.1, 116.1, 68.3,
55.1, 43.9, 21.5, 21.3, 16.4. ESI-MS: m/z=341 [M-H]-.
(2S*,3R*)-1-(4-hydroxyphenyl)-4-methyl-3-methyl-
2-phenylsuccinate (4b): Following the general procedure,
compound 4b was obtained as a white powder after
(3o): Following the general procedure, olefin 2e were
converted for 65%, obtaining compound 3o as a pale
orange oil with 46% of yield (0.170 g) over the converted
olefin. 1H NMR δ 5.07–4.92 (m, 2H), 2.72 (dq, J = 7.1, 8.3
Hz, 1H), 2.62 (td, J = 4.1 8.7 Hz, 1H), 1.64–1.46 (m, 2H),
1.38–1.17 (m, 18H), 1.14 (d, J = 7.1 Hz, 3H), 0.87 (t, J =
6.8 Hz, 3H). 13C NMR δ 174.9, 174.3, 67.8, 67.7, 47.6,
41.1, 31.8, 28.6, 26.5, 22.5, 21.87, 21.85, 21.82, 21.77,
14.3, 14.1. ESI-MS: m/z=287 [M+H]+.
(2S*,3S*)-Dimethyl 2-butyl-3-ethylsuccinate (3p):
Following the general procedure, compound 3p was
obtained as a colorless oil; yield: 92% (0.424 g). H NMR
1
δ 3.64 (s, 3H), 3.63 (s, 3H), 2.70–2.57 (m, 2H), 1.75–1.50
(m, 4H), 1.35–1.09 (m, 4H), 0.84 (t, J = 7.1 Hz, 6H). 13C
8
This article is protected by copyright. All rights reserved.

10.1002/adsc.201701597
Advanced Synthesis & Catalysis
column chromatography on silica gel (CH2Cl2 then
Et2O/CH2Cl2 5:95, in this case the previous extraction with
NaOH 1M / CH2Cl2 was not carried out due to 4b water
solubility); yield: 41% (0.281 g). 1H NMR δ 7.44–7.29 (m,
5H), 6.82–6.69 (m, 4H), 5.06 (hept, J = 6.2 Hz, 1H), 3.96
(d, J = 11.4 Hz, 1H), 3.19 (dq, J = 11.4, 7.3 Hz, 1H), 1.27
(d, J = 6.5 Hz, 3H), 1.25 (d, J = 6.5 Hz, 3H), 1.01 (d, J =
7.3 Hz, 3H). 13C NMR δ 175.3, 172.5, 153.4, 144.4, 136.2,
129.2, 128.7, 128.1, 122.4, 116.0, 68.4, 54.5, 42.9, 21.9,
21.8, 15.6. ESI-MS: m/z=341 [M-H]-.
Chen, W. Sun, C. Xia, Chin. J. Catal. 2010, 31, 1; f) A.
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2009, 1, 28; g) A. Brennfuehrer, H. Neumann, M.
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Salerno, M. Costa, Top. Organomet. Chem. 2006, 10,
1397; j) C. Godard, B. K. Muñoz, A. Ruiz, C. Claver,
Dalton Trans. 2008, 853; k) X.-F. Wu, RSC Adv. 2016,
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Ad hoc synthesis of catalyst A: (bis(2,6-
dimethylphenyl)butane-2,3-
diimine)palladium(II)bis(trifluoroacetate): In a nitrogen
flushed Schlenk tube, equipped with a magnetic stirring
bar, the Pd(TFA)2 (13.3 mg, 0.04 mmol) and THF (0.5
mL) were added in sequence. After the mixture turned in a
red/brown color (20 min), the ligand 1b (11.8 mg, 0.0404
mmol) was added. The mixture was left under stirring for
10 min, turning in a dark orange color. The solvent was
removed under vacuum. The complex A was obtained as a
orange powder; yield: 91% (0.023 g). The NMR spectra
are recorded dissolving the catalyst in 50μL of HFIP and
then adding CDCl3. 1H NMR δ 7.35–7.23 (m, 2H), 7.15 (d,
J = 7.6 Hz, 4H), 2.35 (s, 12H), 2.19 (s, 6H). 13C NMR δ
[4] a) D. M. Fenton, P. J. Steinwand, J. Org. Chem. 1972,
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1990, 739; h) P. Bréchot, Y. Chauvin, D. Commereuc,
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Eur. J. Org. Chem. 2017, 1139.
2
180.3, 163.6 (q, JCF = 38 Hz), 140.6, 130.0, 129.4 (2C),
114.4 (d, 1JCF = 287 Hz), 18.99, 17.5. 19F NMR δ -75.1.
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. FF thanks Prof. Fabio Prati,
Dr. Emila Caselli and Dr. Diego Pinetti of University of Modena
and Reggio Emilia, for useful discussions.
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10.1002/adsc.201701597
Advanced Synthesis & Catalysis
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Advanced Synthesis & Catalysis
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11
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Advanced Synthesis & Catalysis
FULL PAPER
Diastereospecific Bis-Alkoxycarbonylation of 1,2-
disubstituted Olefins Catalyzed by Aryl α-Diimine
Palladium(II) Catalysts
Adv. Synth. Catal. Year, Volume, Page – Page
Diego Olivieri,a Francesco Fini,b* Rita Mazzoni,a
Stefano Zacchini,a Nicola Della Ca’,c Gilberto
Spadoni,d Bartolo Gabriele,e Raffaella Mancuso,e
Valerio Zanottia and Carla Carfagnaa*
12
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