The dba-free Heck-Matsuda reaction was investigated via direct ESI-MS(/MS) monitoring. Palladium species involved in the reduction of Pd(II) during a Wacker type reaction and several dba-free arylpalladium transient complexes were detected and characterized. Based on these findings, a more comprehensible catalytic cycle for this pivotal reaction is suggested.113277-8

Correia, Carlos Roque D

Eberlin, Livia S

Eberlin, Marcos N

Machado, Angelo H L

Milagre, Humberto M S

Sabino, Adão A

Organic & Biomolecular Chemistry

English

Repositorio da Producao Cientifica e Intelectual da Unicamp

Organic &
Biomolecular Chemistry
COMMUNICATION
Cite this: Org. Biomol. Chem., 2013, 11,
3277
Received 22nd January 2013,
Accepted 6th March 2013
DOI: 10.1039/c3ob40142a
www.rsc.org/obc
“Dba-free” palladium intermediates of the
Heck–Matsuda reaction†
Angelo H. L. Machado,a Humberto M. S. Milagre,b,c Livia S. Eberlin,b Adão A. Sabino,b,d
Carlos Roque D. Correia*a and Marcos N. Eberlin*b
The “dba-free” Heck–Matsuda reaction was investigated via direct
ESI-MS(/MS) monitoring. Palladium species involved in the
reduction of Pd(II) during a Wacker type reaction and several
“dba-free” arylpalladium transient complexes were detected and
characterized. Based on these findings, a more comprehensible
catalytic cycle for this pivotal reaction is suggested.
The Heck reaction is recognized as one of the most important
synthetic tools for construction of C–C bonds.1 This pivotal
reaction has found numerous applications due to its rather
mild reaction conditions and versatility. Despite several
impressive demonstrations of its synthetic utility, the reaction
is still under mechanistic investigation.2
Phosphane-free versions of the Heck reaction have also
been attracting interest due to its superior economy, practic-
ability, and experimentally simpler protocols.3 An illustrative
case of the phosphane-free protocols is that in which arenedia-
zonium salts are used as the arylating partner instead of the
more conventional aryl halides and aryl triflates.4 This version
is known as the Heck–Matsuda arylation and has been finding
increasing application in the synthesis of natural products and
biologically active molecules.5 Contrary to the mainstream
Heck reactions, less attention has however been paid to the
understanding of the mechanistic aspects of the Heck reaction
using arenediazonium salts.
To get broad knowledge of a reaction mechanism, it is criti-
cal to fully intercept and characterize most, ideally all inter-
mediates and catalytic species, including even the most
transient species present in the reaction solution at different
periods during its course. Mass spectrometry with direct
infusion of reaction solutions via electrospray ionization
(ESI),6,7 or more recently, via ambient desorption/ionization
techniques8 has been providing a solid bridge between solu-
tion and gas phase chemistries for comprehensive mechanism
investigations.10 These techniques allow rapid and efficient
“fishing” of reactants, intermediates and/or products in their
intact ionic forms, or in protonated or deprotonated forms or
in charge-tagged forms directly to the gas phase. MS and
MS/MS characterization can therefore be performed on the
gaseous ions via the measurement of their m/z values and/or
the structural information provided by their collision induced
dissociation (CID) products.9
We have previously applied ESI-MS(/MS) to investigate the
Heck–Matsuda reaction with arenediazonium salts using
Pd2(dba)3·dba as the catalyst
11 as well as other palladium
mediated reactions.12 Several cationic Pd species present in
the reaction medium were intercepted and characterized, and
a detailed catalytic cycle for this reaction was proposed
(Scheme 1). Complex 4 with dibenzylideneacetone (dba) as a
ligand was assigned as the key catalytically active Pd(II) species
in the olefin insertion step. The catalytic role of the Pd(II)
species such as 2 and 3 in this step has however not been
investigated in “dba-free” media.
Here we report on the ESI-MS(/MS) monitoring of the
Heck–Matsuda reactions with arenediazonium salts using Pd
(OAc)2 as the sole Pd source instead of Pd2(dba)3·dba. An inves-
tigation was therefore undertaken to find the actual catalytic
species present in a “dba-free” medium, and to compare these
results with those obtained when dba is present. These find-
ings provided the basis for an expanded mechanistic view of
this pivotal reaction.
For the Heck–Matsuda reaction with arenediazonium salts,
we have observed that the arylated adducts 8 are obtained in
good yields only when Pd(OAc)2 is pre-mixed in wet aceto-
nitrile with 2,3-dihydrofuran (DHF) prior to the addition of the
remaining DHF, the arenediazonium salt, and the base
(NaOAc).4f In this step, probably the reduction of Pd(II) to Pd(0)
occurs in a way similar to that of the Wacker olefin oxidation.2b
Fig. 1a shows the ESI(+)-MS for the reaction between Pd(OAc)2
†Electronic supplementary information (ESI) available. See DOI:
10.1039/c3ob40142a
aChemistry Institute, University of Campinas – UNICAMP, Campinas, Brazil.
E-mail: roque@iqm.unicamp.br; Fax: +55 19 3521 3023; Tel: +55 19 3521 3086
bThomson Laboratory, University of Campinas – UNICAMP, Campinas, Brazil.
E-mail: eberlin@iqm.unicamp.br; Fax: +55 19 3521 3073; Tel: +55 19 3521 3073
cInstitute of Biosciences, Universidade Estadual Paulista – UNESP, Rio Claro, Brazil
dDepartment of Chemistry, Federal University of Minas Gerais – UFMG, Belo
Horizonte, Brazil
This journal is © The Royal Society of Chemistry 2013 Org. Biomol. Chem., 2013, 11, 3277–3281 | 3277
and DHF in CH3CN 5 min after the reagents were mixed in
stoichiometric amounts. Five major ions were characterized as
key reaction species: 9 of m/z 247 (note that all m/z values are
given for the most abundant 106Pd isotopologue ion), 14 of m/z
275, 15 of m/z 234, 16 of m/z 327 and 17 of m/z 286. The pro-
posed structures are supported by the characteristic isotopolo-
gue distribution of these Pd species and by the dissociation
chemistries observed via ESI-MS/MS experiments (see ESI† for
details).
The dissociation observed for 9 (Fig. S1†) indicates that this
intermediate is formed by ligand exchange between AcO− and
MeCN on Pd(OAc)2. This is probably the first step of the
Wacker type Pd reduction reaction (Scheme 2). Complexes 14
and 15 (Fig. S2 and S3†) differ only by the number of MeCN
ligands (Scheme 2), and were identified as the oxidative
addition product between Pd(0) solvated species and DHF, the
product of the Wacker oxidation of DHF. Although the iso-
meric 13 and 14 intermediates would be undistinguishable by
ESI-MS, the fragment of m/z 206 – detected due to the loss of
the 2H-furanyl radical from the ion of m/z 275 – supports struc-
ture 14. We rationalize that 14 is connected to 9 by the com-
plexes shown in Scheme 2, which could not be detected by
Scheme 1 Previously reported catalytic cycle for the Heck–Matsuda reaction
based on ESI-(+)-MS/MS monitoring. (Structures highlighted in blue correspond
to intermediates characterized by ESI(+)-MS/MS experiments.)
Fig. 1 ESI(+)-MS of the reaction solution of the Wacker type palladium
reduction after (a) 5 min and (b) 30 min.
Scheme 2 Proposed mechanism for the Wacker type Pd(II) reduction mediated by DHF.
Communication Organic & Biomolecular Chemistry
3278 | Org. Biomol. Chem., 2013, 11, 3277–3281 This journal is © The Royal Society of Chemistry 2013
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ESI(+)-MS. The failure to detect 13 suggests that reductive
elimination is faster than oxidative addition which forms 14.13
Complexes 16 and 17 seem to be formed by ligand exchange
promoted by DHF in complexes 14 and 15, followed by inser-
tion of DHF into the bond between Pd and π-allyl (Scheme 2).
Since palladium black forms in the reaction solution, the
behavior of the Pd species was monitored in the reaction
solution by ESI(+)-MS during the first 30 min. A continuous
increase in the abundance of 9 (relative to intermediates 14,
15, 16 and 17, Fig. 1b) as well as the detection of Pd species of
higher m/z values in smaller abundances (m/z 429, 470, 511
and 552) were observed. These new species were selected for
ESI(+)-MS/MS characterization, and their dissociation was
found to converge to the ion of m/z 429 by MeCN losses
(Fig. S6–S9†). The spectra for the ion of m/z 429 suggested its
connection with 17 (m/z 327) due to the loss of both MeCN
(41 Da) and, most probably, carbamic acid (61 Da).
Next, the crucial oxidative addition step between
4-MeOPhN2
+BF4
− and the Pd(0) species was further investi-
gated by the addition of 0.5 eq. of the arenediazonium salt to
the initial reaction solution. As Fig. 2a shows, the population
of the Pd-ions 14, 15, 16 and 17 decreased and the most rele-
vant ions detected were 4-MeOPhN2
+ of m/z 135, 18 of m/z 148
(nucleophilic substitution of N2 by MeCN) and 19 of m/z 324,
which appears to represent a key reaction intermediate. Inter-
mediate 19 was therefore selected and dissociated. Its dis-
sociation chemistry supports a route for formation of 19
involving complexation between the Heck adduct and the pal-
ladium hydride solvated by MeCN (Fig. S13†).
The ESI(+)-MS for the reaction solution after addition of the
remaining 0.5 eq. of 4-MeOPhN2
+BF4
− (Fig. 2b) showed a
decrease in the abundance of 19 with the respective increase
of that for 3. This dynamic change in the ionic composition of
the reaction solution snapshoted by ESI(+)-MS can be rational-
ized by the oxidative addition of 4-MeOPhN2
+ to the Pd(0)
species formed by palladium hydride decomposition pro-
moted by BF4
−. The addition of the arenediazonium salt
avoids formation of the palladium black observed in the initial
Pd(OAc)2 and DHF dissolution in MeCN. Another interesting
trend was the decreasing of 16 of m/z 327 and 17 of m/z 286
Fig. 2 ESI(+)-MS of dba-free arylpalladium complexes and its olefin insertion
with DHF.
Scheme 3 Updated catalytic cycle for the Heck–Matsuda reaction.
Organic & Biomolecular Chemistry Communication
This journal is © The Royal Society of Chemistry 2013 Org. Biomol. Chem., 2013, 11, 3277–3281 | 3279
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and the detection and characterization of 20 of m/z 139. The
structure of 20 is supported by its CID chemistry (Fig. S14†)
and its formation likely proceeds via nucleophilic addition of
DHF to the π-allyl complex 14. The detection of 20 also corro-
borates with the proposed structure of the Pd intermediates 16
and 17.
Notable was also the detection of the oxidative addition
complex 3 and the palladium hydride complex 19, which
demonstrates the participation of “dba-free” species in the
catalytic cycle of the Heck–Matsuda reaction. Therefore, “dba-
free” species may also be catalytically active even when
Pd2(dba)3 is applied as a Pd source. These results prompted us
to redraw our earlier proposed catalytic cycle11 in a way that
“dba-free” arylpalladium complexes could bypass the dba/
MeCN ligand exchange to promote the carbopalladation step
that forms the final Heck–Matsuda adduct 8 (Scheme 3).
The previously observed stability of the dba-containing
complex 4 as compared to those of 2 and 3 can provide a quali-
tative measurement of the relative reactivity between these
species.11 Assuming that the olefin insertion step to dba-free
arylpalladium complexes 2 and 3 is fast, the concentration of 2
and 3 tends to decrease when compared to that of 4. The prob-
ability of dba-free Pd to collapse and precipitate as palladium
black is therefore higher when compared to those bonded to
dba. This scenario suggests an important reservoir role for 4,
which is responsible to deliver Pd(0) slowly to the reaction
pathway by arylation of dba followed by π-elimination and
basic palladium hydride decomposition to yield “naked” Pd(0)
species such as Pd(CH3CN)4.
14
Conclusions
Reaction monitoring via ESI(+)-MS(/MS) has provided evidence
for the participation of “dba-free” arylpalladium intermediates
in the olefin insertion step of the Heck–Matsuda reaction with
arenediazonium salts using Pd(OAc)2 as the palladium source.
This new mechanistic information prompted us to redraw an
expanded view of the Heck catalytic cycle, bringing new
insights into this pivotal Pd mediated transformation.
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Organic & Biomolecular Chemistry Communication
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Dba-free" Palladium Intermediates Of The Heck-matsuda Reaction."

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Dba-free" Palladium Intermediates Of The Heck-matsuda Reaction."

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