Chemo-, regio- and stereoselective heck arylation of allylated malonates: Mechanistic insights by ESI-MS and synthetic application toward 5-arylmethyl-γ-lactones

Article abstract of DOI:10.1021/ol502529v

We describe herein a general method for the controlled Heck arylation of allylated malonates. Both electron-rich and electron-poor aryldiazonium salts were readily employed as the aryl-transfer agents in good yields and in high chemo-, regio-, and stereoselectivity without formation of decarboxylated byproducts. Reaction monitoring via ESI-MS was used to support the formation of chelated Pd species through the catalytic cycle. Additionally, some Heck adducts were successfully used in the total synthesis of pharmacologically active γ-lactones.

Full text of DOI:10.1021/ol502529v

Letter
pubs.acs.org/OrgLett
Chemo‑, Regio- and Stereoselective Heck Arylation of Allylated
Malonates: Mechanistic Insights by ESI-MS and Synthetic Application
toward 5‑Arylmethyl-γ-lactones
Caio C. Oliveira,† Marcelo V. Marques,‡ Marla N. Godoi,§ Thaís Regiani,§ Vanessa G. Santos,§
Emerson A. F. dos Santos,† Marcos N. Eberlin,§ Marcus M. Sa,‡ and Carlos R. D. Correia*,†
́
†Instituto de Química, Universidade Estadual de Campinas-UNICAMP, Campinas, SP 13083-970, Brazil
‡Departamento de Química, Universidade Federal de Santa Catarina, Florianop
́
olis, SC 88040-900, Brazil
§Laborator
́
io ThoMSon de Espectrometria de Massas, Universidade Estadual de Campinas-UNICAMP, Campinas, SP 13083-970,
Brazil
S
* Supporting Information
ABSTRACT: We describe herein a general method for the controlled
Heck arylation of allylated malonates. Both electron-rich and electron-poor
aryldiazonium salts were readily employed as the aryl-transfer agents in
good yields and in high chemo-, regio-, and stereoselectivity without
formation of decarboxylated byproducts. Reaction monitoring via ESI-MS
was used to support the formation of chelated Pd species through the
catalytic cycle. Additionally, some Heck adducts were successfully used in
the total synthesis of pharmacologically active γ-lactones.
Scheme 1. Heck Reactions with Allylated Malonates
he Heck reaction has been a pivotal tool for the creation
Tof new C−C bonds in chemical synthesis. Its versatility
has been demonstrated by many novel methods based on
Heck-type reactions as well as its use as a key step in the total
synthesis of complex molecules.1 Despite its broad application,
a common feature of this reaction is the low selectivity due to
uncontrolled migratory insertion and β-elimination when
nonelectronic biased olefins are used.2 In this context, we
have demonstrated that the catalytic pathways involved in the
Heck reactions with aryldiazonium salts (Heck−Matsuda
reaction)3 could be successfully controlled by substrates bearing
chelating groups, such as the carbonyl group, thus allowing the
regio- and stereoselective arylation of allylic acetates and amine
derivatives.4
We describe herein our efforts to apply the substrate-
directable Heck−Matsuda reactions to the synthetically
challenging allyl malonates (1 and 4, Scheme 1). α-
Cinnamylated malonates such as 3 and 7 are useful substrates
for the synthesis of carbo- and heterocycles,5 but somewhat
surprisingly, there are a limited number of general methods for
their synthesis.6
In 2009, Su and co-workers described the combination of 1
with carboxylic acids as a suitable method for the synthesis of
cinnamylated malonates 3. They employed a Pd-catalyzed
decarboxylative Heck reaction, although only ortho-anisic acids
2 were truly effective.7 Additionally, Doucet and co-workers
have described the Heck reaction of 4 with aryl bromides 5 to
give cinnamylated malonates 7 in good yields and selectivity.
However, formation of decarboxylated byproducts 8 was often
observed, especially when ortho-substituted bromides were
employed.8
To our delight, our previous reaction conditions optimized
for the arylation of allylic esters4a also proved suitable for the
allylated malonate 4. Treatment of 4 in an open-flask vessel
with 1.2 equiv of 4-methoxyphenyldiazononium salt (9a), 8
Received: August 27, 2014
Published: September 23, 2014
© 2014 American Chemical Society
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Organic Letters
Letter
mol % of Pd(dba)2 in benzonitrile, and freshly powdered
NaOAc as the base, at room temperature for 1 h, furnished the
cinnamylated malonate 7a in 91% yield with an 88:12 ratio in
favor of the linear (l) versus the branched (b) regioisomer 10.
After crystallization, the E-isomer 7a could be isolated in pure
form (Scheme 2).
aryldiazonium salts (the Japp−Klingemman reaction) which
provides the azo products 11 and 12 (Scheme 3).9 Therefore,
these observations place the current method in a privileged
position regarding the synthesis of structurally diverse
cinnamylated malonates.
Scheme 3. Undesired Japp−Klingemman Reaction
Scheme 2. Stereoselective Heck−Matsuda Reaction for 7
To rationalize the mechanism of this substrate-directable
Heck−Matsuda reaction, the reaction outcome was monitored
by electrospray ionization−mass spectrometry (ESI-MS).10
Because arylation proceeds by a cationic mechanism, it is
possible to follow the transformation by ESI-MS without the
need of additives or charge tags. The reaction between allylated
malonate 4 and the aryldiazonium 9a, catalyzed by Pd(dba)2, in
benzonitrile was monitored periodically until the starting
material 4 was consumed. Aliquots of the reaction medium
(1 μL) were taken and diluted in acetonitrile (1 mL) with 0.1%
of formic acid and ESI(+)-MS recorded every 5 min (Figure
1).11 A very clean ESI mass spectrum was observed 5 min after
To evaluate the scope of the substrate-directable Heck−
Matsuda reaction, we extended the conditions described above
to several electronically and sterically distinct aryldiazonium
salts 9 (Scheme 2). In general, arylations were highly selective
when electron-deficient and/or ortho-substituted aryldiazonium
salts were used. These results support our previous hypothesis4
that more electrophilic cationic arylpalladium species provides
more tightly chelated intermediates, thus resulting in higher
selectivities. Functional groups amenable to further derivatiza-
tion, such as nitro (7q−t), cyano (7p), hydroxyl (7h), and
halogen (7g,i−k,o), were well tolerated. The corresponding
Heck products were obtained in good yields and stereo-
selectivity higher than 92:8 in favor of the linear isomer with E-
configuration, although formation of the Z-isomer in very small
amounts could be inferred from the analysis of the crude
Figure 1. Monitoring the Heck−Matsuda reaction by ESI-MS.
addition of 4-methoxybenzenediazonium salt (9a), which
supported the formation of a cationic arylpalladium species
coordinated to three molecules of acetonitrile (13, m/z 336)
and an interesting alkylpalladium intermediate whose cationic
Pd seems chelated by both carboxyl groups of the malonate
moiety (14, m/z 426). More informative was the observation of
a qualitative relationship between the consumption of 14 and
an increase of relative abundance of the ions corresponding to
the Heck−Matsuda adduct 7a (m/z 301 and m/z 342, due to
simultaneous detection of Na+ or Na+/acetonitrile, respec-
tively). Finally, after 60 min, the ion attributed to 14 (m/z 426)
nearly disappeared, in accordance with the reaction time
observed in the laboratory (Figure 1)
1
reaction by H NMR spectroscopy.
We also noted that running the Heck−Matsuda reaction in
shorter times at room temperature avoids the occurrence of
two intrinsic and undesired side reactions, namely, the
decarboxylation of cinnamylated malonates 7 to furnish esters
8 and the nucleophilic addition of malonate derivatives to
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To support the role of intermediate 14 in the Heck−
Matsuda reaction, and its assignment as species chelated by
both carboxyl groups, a few control experiments were
performed as described in Scheme 4. Because the dba ligand
Scheme 5. Catalytic Cycle for the Formation of 7 Based on
ESI-MS
Scheme 4. Probing the Role of Intermediate 14 in the
Substrate-Directable Heck−Matsuda Reaction
In the present study, dba do not seem to have any relevant
stabilization role because of the coordinating groups present in
the olefin. Indeed, an ion of m/z 341 [PdH(dba)], previously
identified by us as an important intermediate for the Heck−
Matsuda reaction with 2,3-dihydrofuran,10a was not intercepted
in the present reaction. This apparent low influence of dba can
be explained by the preferential transference of PdH species to
a previously formed Heck adduct 7 (H − characterized by ESI
(+)-MS, see the Supporting Information).4c We hypothesize
that PdH transference might operate as a potential route for the
isomerization of the major linear E product into the very minor
Z isomer. Formation of the branched isomer 10 in minor
amounts can be rationalized by the noncarbonyl-assisted
insertion of the cationic arylpalladium 13 onto allylated
malonate 4, which is in accordance with the expected
regioselectivity in the carbopalladation of alkyl-substituted
olefins.12
To demonstrate further the synthetic and strategic potential
of this method to prepare useful compounds, we use it to
developed a straightforward route to pharmacologically active
5-arylmethyl-γ-lactones 25. The synthesis started with the
epoxidation of the cinnamylated malonates 7 with aqueous
Oxone13 in a two-phase system (to avoid byproducts from
overoxidation) to give the corresponding epoxides 23 cleanly
with yields ranging from 85 to 95% (1H NMR yield). To
prevent decomposition of epoxides 23, in particular those
containing electron-donating groups in the aryl moiety, the
routes were optimized using the crude reaction products in the
next two steps. They consisted of hydrogenolysis of the
benzylic C−O bond with H2−Pd/C in THF followed by a
microwave-assisted tandem lactonization/Krapcho decarboxy-
seems to have no effective role in the reaction, the catalyst
Pd(dba)2 was replaced by Pd(OAc)2 (reduced to Pd(0) with a
CO atmosphere). As expected, the Heck product 7a was
isolated in 75% yield with virtually the same selectivity
(90l:10b) (Scheme 4a).
Heck arylation of the unsaturated monoester 15 showed
decreased l:b selectivity, providing compound 16 along with
several isomeric products originated from double bond
migration (Scheme 4b). Similar behavior was observed when
the distance between the alkene moiety and the carboxyl
groups was increased by using the homologous analogues 17
and 18 (Scheme 4c). Finally, introduction of an α-methyl
group in the malonate portion favored formation of a chelate-
type intermediate by a Thorpe−Ingold effect to give the
expected arylated malonates 22 with excellent l:b selectivity
regardless of the electronic nature of the aryldiazonium salt
employed (Scheme 4d).
Based on the data collected, we propose a catalytic cycle for
this Heck reaction as summarized in Scheme 5 starting with the
oxidative addition of Pd(0) to the aryldiazonium salt followed
by N2 extrusion to generate the cationic arylpalladium B
[similar to the intermediate 13 (m/z 336) in Figure 1].
Chelation of 13 by allylated malonate 7 leads to palladabicycle
C, which then directs the insertion of the aryl group to the
terminal carbon-forming D, which is analogous to 14 (m/z
426) in Figure 1. Rotation of the benzylic center followed by a
favored β-elimination of Pd−H from syn-E produces the linear
Heck product (E)-7a and the palladium hydride G, which is
decomposed by the base to regenerate the catalyst.
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(2) For selective β-eliminations in Heck reactions, see: (a) Werner, E.
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lation of the resulting secondary alcohols 24 to provide the 5-
arylmethyl-γ-lactones 25 after a single column chromatography
purification, in overall yields ranging from 42 to 59% starting
from the cinnamylated malonates 7 (Scheme 6). Lactones 25a
Scheme 6. Synthesis of 5-Arylmethyl-γ-lactones 25
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In summary, we have developed an efficient and straightfor-
ward method for the arylation of allylated malonates using the
Pd-catalyzed Heck−Matsuda reaction with aryldiazonium salts.
All transformations were carried out under open flask
conditions, and the products were obtained with high
chemo-, regio-, and stereocontrol. Mechanistic investigations
by ESI-MS reation monitoring supported the involvement of an
interesting chelated intermediate consisted of Pd(II)+ bound to
both carboxyl groups present in the substrate. Finally, the Heck
adducts 7 were readily transformed into 5-arylmethyl-γ-lactones
25 possessing relevant pharmacological properties.
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ASSOCIATED CONTENT
* Supporting Information
Experimental details, characterization data for the new
compounds, and spectra. This material is available free of
charge via the Internet at http://pubs.acs.org.
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AUTHOR INFORMATION
Corresponding Author
■
*E-mail: roque@iqm.unicamp.br.
Notes
Folgado, L.; Gomez-Canas, M.; Gomez-Ruiz, M.; Fernandez-Ruiz, J.;
́
́
́
̃
Elguero, J.; Jagerovic, N.; Serrano, A.; Goya, P.; de Fonseca, F. R.
Bioorg. Med. Chem. 2013, 21, 1708.
The authors declare no competing financial interest.
(10) (a) Sabino, A. A.; Machado, A. H. L.; Correia, C. R. D.; Eberlin,
M. N. Angew. Chem., Int. Ed. 2004, 43, 2514; Angew. Chem. 2004, 116,
2568. (b) Machado, A. H. L.; Milagre, H. M. S.; Eberlin, L. S.; Sabino,
A. A.; Correia, C. R. D.; Eberlin, M. N. Org. Biomol. Chem. 2013, 11,
3277. (c) Fiebig, L.; Schlorer, N.; Schmalz, H.-G.; Schafer, M. Chem.
ACKNOWLEDGMENTS
■
We thank the Sao Paulo Research Foundation (FAPESP, Gran
̃
Nos. 2011/23832-6 and 2013/07600-3), the Brazilian National
Research Council (CNPq), and the Brazilian Coordination for
the Improvement of Higher Education Level Personnel
(CAPES) for financial support and fellowships.
̈
̈
Eur. J. 2014, 20, 4906. (d) Santos, V. G.; Godoi, M. N.; Regiani, T.;
Gama, F. H. S.; Coelho, M. B.; de Souza, R. O. M. A.; Eberlin, M. N.;
Garden, S. J. Chem.Eur. J. 2014, 20, 12808.
(11) Acetonitrile was used to dilute the reaction samples due to the
high boiling point of benzonitrile (191 °C).
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