Unprecedented substoichiometric use of hazardous aryl diazonium salts in the Heck-Matsuda reaction via a double catalytic cycle

Article abstract of DOI:10.1021/ol200752x

The first Heck-Matsuda reaction using a catalytic amount of diazonium salts has been discovered. The reaction proceeds through an unprecedented double catalytic cycle in which the electrophile is in situ generated through the reaction advancement. This concept features mild and safe conditions as hazardous aryl diazonium salts are not isolated anymore. Importantly, this sustainable procedure generates only environmentally friendly byproduct such as t-BuOH, H₂O, and N₂.

Full text of DOI:10.1021/ol200752x

ORGANIC
LETTERS
2011
Vol. 13, No. 10
2646–2649
Unprecedented Substoichiometric Use of
Hazardous Aryl Diazonium Salts in the
Heck-Matsuda Reaction via a Double
Catalytic Cycle
Franc-ois Le Callonnec, Eric Fouquet, and Franc-ois-Xavier Felpin*
ꢀ
Universite de Bordeaux, UMR CNRS 5255, Institut des Sciences Moleculaires,
351 Cours de la Liberation, Talence, 33405 France
ꢀ
ꢀ
fx.felpin@ism.u-bordeaux1.fr
Received March 21, 2011
ABSTRACT
The first Heck-Matsuda reaction using a catalytic amount of diazonium salts has been discovered. The reaction proceeds through an
unprecedented double catalytic cycle in which the electrophile is in situ generated through the reaction advancement. This concept features
mild and safe conditions as hazardous aryl diazonium salts are not isolated anymore. Importantly, this sustainable procedure generates only
environmentally friendly byproduct such as t-BuOH, H2O, and N2.
The Heck-Mizoroki reaction has become a standard in
the toolbox of every synthetic chemist. The simultaneous
observation, in the laboratories of Mizoroki1 and Heck,2
that aryl halides could be coupled with olefins in the
presence of a palladium catalyst, has opened the way for
40 years of impressive achievements directed at the devel-
opment of numerous efficient catalytic systems.3 In Octo-
ber 2010, the Nobel Prize in chemistry was awarded to
Richard F. Heck in recognition of his discovery.4
A far less explored variant of this coupling, known as the
HeckÀMatsuda reaction, entails the use of aryl diazonium
salts as highly reactive aryl halide surrogates (Scheme 1).5
The superelectrophile properties of aryl diazonium salts
allows the reaction to proceed under mild conditions (T <
60 °C), without the need of ligand, and even sometimes,
base. The simple and efficient experimental procedure
features many advantages, including energy, cost, and
waste benefits that are of interest for the development of
sustainable processes.
Scheme 1. General Representation of the HeckÀMatsuda Re-
action
(1) Mizoroki, T.; Mori, K.; Ozaki, A. Bull. Chem. Soc. Jpn. 1971, 44,
581–582.
(2) Heck, R. F.; Nolley, J. P., Jr. J. Org. Chem. 1972, 37, 2320–2322.
(3) (a) Beletskaya, I. P.; Cheprakov, A. V. Chem. Rev. 2000, 100,
3009–3066. (b) Whitcombe, N. J.; Hii, K. K.; Gibson, S. E. Tetrahedron
2001, 57, 7449–7476. (c) Handbook of Organopalladium Chemistry for
Organic Synthesis; Negishi, E. I., Ed.; Wiley: New York, 2002; Vol. 2.
(4) The Nobel Prize in Chemistry 2010 was awarded jointly to
Richard F. Heck, Ei-ichi Negishi and Akira Suzuki.
Aryl diazonium salts have been discovered in the middle
of the 19th century by Johann Peter Griess who was
working on azo-compounds as dyes and pigments.6 They
are a class of superelectrophile with the common structure
of R-N2X where R is an aryl or heteroaryl fragment and X
is a weakly nucleophilic organic or inorganic anion. A
number of diazonium salts are commercially available;
~
(5) (a) Roglans, A.; Pla-Quintana, A.; Moreno-Manas, M. Chem.
Rev. 2006, 106, 4622–4643. (b) Taylor, J. G.; Venturini Moro, A.;
Correia, R. C. D. Eur. J. Org. Chem. 2011, 1403–1428. (c) Felpin,
F.-X.; Nassar-Hardy, L.; Le Callonnec, F.; Fouquet, E. Tetrahedron
2011, 67, 2815–3831.
(6) Griess, P. Liebigs Ann. Chem. 1858, 106, 123–125.
r
10.1021/ol200752x
Published on Web 04/25/2011
2011 American Chemical Society

however, the high nucleofugic properties of the diazonium
function makes these compounds potentially hazardous,
especially on large scale. By the way, whenever aryl
diazonium salts have been involved in several industrial
processes, including a HeckÀMatsuda transformation for
the preparation of herbicide Prosulfuron at Syngenta,7
safety issues hampered further developments. Indeed, the
stability of aryl diazonium salts is mostly dependent on the
associated counterion, although the aryl structure should
also be considered. For instance, while aryl diazonium
chlorides8 and acetates are unstable above 0 °C, their
tetrafluoroborate,9 tosylate,10 and disulfonimide11 coun-
terparts are usually more stable crystalline salts. However,
as the stability cannot be anticipated due to the absence of
well-defined rules, safety issues need to be addressed for
chemists who do not want to play Russian roulette.
palladium intermediates bear a positive charge during
the catalytic cycle.15 This uncommon feature renders very
active the intermediates D to F and optional the use of a
base. As a consequence, in the absence of a base, one molar
equivalent of a nontrapped acid (HX) is generated per
equivalent of olefin C formed.
Scheme 2. Catalytic Cycle of the HeckÀMatsuda Reaction
HeckÀMatsuda reactions have been mostly carried out
with diazonium salts having a tetrafluoroborate anion.12
Crystalline salts are typically prepared from the corre-
sponding aniline by action of a nitrite in the presence of
fluoroboric acid or BF3 Et2O.13 A safer protocol, invol-
3
ving the in situ preparation of diazonium salts, has been
elegantly proposed by Andrus and co-workers.14 How-
ever, the procedure still required the use of an equimolar
quantity of BF3 Et2O and furnished styrene type com-
3
pounds with quite modest yields (17À62%).
With the aim of developing a safe and environmentally
benign strategy, we sought for a conceptually novel ap-
proach. Our idea grew up after a detailed survey of the
mechanism involved in the HeckÀMatsuda reaction
(Scheme 2). Indeed, it has been well established that
We also realized that a stoichiometric use of the same acid
was also required for the prior formation of the diazonium
salt from the corresponding aniline G (Scheme 3).
(7) (a) Baumeister, P.; Meyer, W.; Oertle, K.; Seifert, G.; Steiner, H.
Chimia 1997, 51, 144–146. (b) Baumeister, P.; Seifert, G.; Steiner, H.
EP0584043, 1992.
(8) Kikukawa, K.; Nagira, K.; Wada, F.; Matsuda, T. Tetrahedron
1981, 37, 31–36.
Scheme 3. General Preparation of Diazonium Salts
(9) Flood, D. T. Org. Synth. 1943, 2, 295–298.
(10) Filimonov, V. D.; Trusova, M.; Postnikov, P.; Krasnokutskaya,
E. A.; Lee, Y. M.; Hwang, H. Y.; Kim, H.; Chi, K.-W. Org. Lett. 2008,
10, 3961–3964.
(11) (a) Barbero, M.; Crisma, M.; Degani, I.; Fochi, R.; Perracino, P.
Synthesis 1998, 1171–1175. (b) Artuso, E.; Barbero, M.; Degani, I.;
Dughera, S.; Fochi, R. Tetrahedron 2006, 62, 3146–3157.
(12) For some relevant examples, see: (a) Darses, S.; Pucheault, M.;
With these observations in mind, we anticipated that a
catalytic amount of HX could be used in a cascade
diazonium formation-Heck coupling process, according
to the following unprecedented double catalytic cycle
(Scheme 4). In the presence of t-BuONO aniline G would
be transformed into its corresponding hydroxydiazene H with
the concomitant formation of t-BuOH. Treated by a catalytic
amount of an acid HX, the hydroxydiazene H would give the
diazonium salt A. A standard palladium-catalytic cycle, in-
volving an oxidative addition, an olefin insertion, and a
reductive elimination, would furnish the targeted coupling
product F as well as both Pd(0) and acid catalysts necessary
for each catalytic cycle. As the only byproduct formed would
be t-BuOH, H2O, and N2, such an approach should be of
great interest toward the quest of sustainable processes.
Pursuing our challenging hypothesis, we initially fo-
cused on 4-nitroaniline 1a as model substrate since nitro-
substituted aryl diazonium salts frequently failed to parti-
cipate in HeckÀMatsuda reactions16 due to a high tendency
^
Genet, J.-P. Eur. J. Org. Chem. 2001, 1121–1128. (b) Selvakumar, K.;
Zapf, A.; Spannenberg, A.; Beller, M. Chem.;Eur. J. 2002, 8, 3901–
3906. (c) Severino, E. A.; Costenaro, E. R.; Garcia, A. L. L.; Correia,
C. R. D. Org. Lett. 2003, 5, 305–308. (d) Dai, M.; Liang, B.; Wang, C.;
Chen, J.; Yang, Z. Org. Lett. 2004, 6, 221–224. (e) Garcia, A. L. L.;
Carpes, M. J. S.; De Oca, A. C. B. M.; dos Santos, M. A. G.; Santana,
C. C.; Correia, C. R. D. J. Org. Chem. 2005, 70, 1050–1053. (f) Pastre,
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Silva, K.; Godoi, M. N.; Correia, C. R. D. Org. Lett. 2007, 9, 2815–2818.
(h) Cesar-Pastre, J.; Roque Duarte Correia, C. Adv. Synth. Catal. 2009,
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351, 1217–1223. (i) Schmidt, B.; Holter, F. Chem.;Eur. J. 2009, 15,
€
11948–11953. (j) Schmidt, B.; Holter, F.; Berger, R.; Jessel, S. Adv. Synth.
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Catal. 2010, 352, 2463–2473. (k) Stern, T.; Ruckbrod, S.; Czekelius, C.;
Donner, C.; Brunner, H. Adv. Synth. Catal. 2010, 352, 1983–1992. (l) Taylor,
J. G.; Correia, C. R. D. J. Org. Chem. 2011, 76, 857–869.
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(13) (a) Schiemann, G.; Winkelmuller, W. Org. Syntheses 1943, 2,
299–302. (b) Doyle, M. P.; Bryker, W. J. J. Org. Chem. 1979, 44, 1572–
1574. For an interesting alternative protocol, see: Schmidt, B.; Berger,
€
R.; Holter, F. Org. Biomol. Chem. 2010, 8, 1406–1414.
(14) Andrus, M. B.; Song, C.; Zhang, J. Org. Lett. 2002, 4, 2079–
2082.
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M. N. Angew. Chem., Int. Ed. 2004, 43, 2154–2158. (b) Pla-Quintana, A.;
Roglans, A. ARKIVOC 2005, ix, 51–62.
Org. Lett., Vol. 13, No. 10, 2011
2647

Table 1. Screening of Various Acids
Scheme 4. General Strategy for a Double Catalytic Cycle
entry
acid
yield (%)a
1
BF3 Et20
60
47
20
12
54
13
87
90
84
97
3
2
HBF4
3
Diphenylphosphate
H3PO4
4
5
H2SO4
6
CH3CO2H
7
p-Toluenesulfonic acid
Camphorsulfonic acid
MeSO3H
8
9
10b
MeSO3H
a Yields of isolated products. b Anisole (0.5 equiv) was used as
additive.
Having an optimized protocol in hand, we first screened
a variety of nitro-substituted anilines for reaction with
methyl acrylate (Table 2). As already outlined, we selected
nitro-based anilines due to the reluctance of the corre-
sponding diazonium salts to achieve HeckÀMatsuda cou-
pling. Moreover, we also kept in mind that 2-nitrophenyl
acrylates can be further transformed into heterocycles
following our Heck-Reduction-Cyclization (HRC)
strategy.19 To our great pleasure, we observed that, in
many cases, anisole can be omitted. All type of nitro-
substituted anilines, bearing electron-poor or electron-rich
functional groups, gave indifferently high yields of the
corresponding cross-coupled products (entries 1À8). We
also observed that ortho-substituted anilines were effi-
ciently reacted with methyl acrylate (entries 3À11). These
results are of importance since, in palladium chemistry,
diazonium salts are frequently sensitive to steric hindrance.
As a consequence, ortho-substituted partners often failed
to give high yields of coupled products.
We also successfully screened anilines that do not bear a
nitro group (entries 9À12). As of particular note is the
perfect chemoselectivity at the diazonium functionality as
leaving group when bromo-substituted anilines are involved
in the Heck coupling (entries 8À9). This feature opens
opportunities for further selective functionalization at the
bromo group, especially with palladium-based chemistry.20
The lower yield obtained with 2-methyl aniline is not yet fully
understood, but volatility of the corresponding coupling
product renders difficult the purification step (entry 10).
Considering the role of anisole, we assume that it plays a
to decompose, even violently sometimes! This instability has
been ascribed to the high redox potential and a preference for
a homolytic dediazonization pathway.17 Our optimization
studies started with the screening of a variety of acids (20 mol
%) in order to evaluate the influence of the acidity and/or the
nature of the counterion (Table 1). We selected Pd(OAc)2 as
the palladium source and methanol as solvent on the basis of
our previous studies in the field.18 To our great surprise the
tetrafluoroborate anion (entries 1À2) was not the most
effective counterion whatever the source of the acid (i.e.,
HBF4 and BF3 Et2O), although it has been the most used in
3
the literature. Phosphoric, sulfuric and carboxylic acids were
also useless acids for this transformation (entries 3À6).
Fortunately, we observed that sulfonic acids were very
efficient at only 25 °C, whatever their structure (entries
7À10). Finally, we selected MeSO3H as the acid of choice
for our further studies since it is the less expensive sulfonic
acid commercially available, and it can be easily recovered by
distillation at the end of the reaction. The acid loading could
be lowered to 10 mol %; in that case, however, higher
reaction times were required. We also screened a variety of
additives to evaluate their impact on the reaction outcome.
After considerable experimentations, we found that almost a
quantitative yield can be reached by using anisole as additive
(entry 10).
(16) (a) Kikukawa, K.; Nagira, K.; Wada, F.; Matsuda, T. Tetra-
hedron 1981, 37, 31–36. (b) Sengupta, S.; Bhattacharyya, S. J. Chem.
Soc., Perkin Trans. 1 1993, 1943–1944. (c) Priego, J.; Carretero, J. C.
Synlett 1999, 1603–1605. (d) Perez, R.; Veronese, D.; Coelho, F.;
Antunes, O. A. C. Tetrahedron Lett. 2006, 47, 1325–1328.
(17) Yasui, S.; Fujii, M.; Kawano, C.; Nishimura, Y.; Shioji, K.;
Ohno, A. J. Chem. Soc., Perkin Trans. 2 1994, 177–183.
(18) (a) Felpin, F.-X.; Fouquet, E.; Zakri, C. Adv. Synth. Catal. 2008,
350, 2559–2565. (b) Felpin, F.-X.; Miqueu, K.; Sotiropoulos, J.-M.; Fouquet,
E.; Ibarguren, O.; Laudien, J. Chem.;Eur. J. 2010, 16, 5191–5204.
(19) (a) Felpin, F.-X.; Ibarguren, O.; Nassar-Hardy, L.; Fouquet, E.
J. Org. Chem. 2009, 74, 1349–1352. (b) Felpin, F.-X.; Coste, J.; Zakri, C.;
Fouquet, E. Chem.;Eur. J. 2009, 15, 7238–7245. (c) Ibarguren, O.;
Zakri, C.; Fouquet, E.; Felpin, F.-X. Tetrahedron Lett. 2009, 50, 5071–
5074. (d) Laudien, J.; Fouquet, E.; Zakri, C.; Felpin, F.-X. Synlett 2010,
1539–1543.
(20) Taylor, R. H.; Felpin, F.-X. Org. Lett. 2007, 9, 2911–2914.
2648
Org. Lett., Vol. 13, No. 10, 2011

Table 2. Scope of the Reaction
Scheme 5. Coupling with Butyl Acrylate
Scheme 6. Synthesis of Quinolone 5 by the HRC Strategy
In summary, we have described the first HeckÀMatsuda
reaction using a substoichiometric amount of diazonium
salt through an uncovered double catalytic cycle. Our pro-
tocol features very mild conditions, and generates only
environmentally benign byproduct such as t-BuOH, H2O,
and N2. From a safety point of view, our approach does not
require the isolation of hazardous aryl diazonium salts as
they are in situ catalytically generated throughout the reac-
tion advancement from the corresponding anilines.21
Although we are still working on the improvement of the
turnover number and the turnover frequency of our proto-
col, we have validated the challenging proof-of-concept
stage. We believe that such a simple and safe methodology
would initiate a growing interest for the chemistry of diazo-
nium salts. Further developments in this area are actively
pursued in our laboratory and will be reported in due course.
a Yields of isolated products. b Pd(OAc)2 (4.4 mol %) was used.
Acknowledgment. We gratefully acknowledge the
ꢀ
“Universite de Bordeaux”, the “Centre National de la
crucial role in stabilizing palladium species and especially
cationic intermediates involved in the catalytic cycle.
Recherche Scientifique (CNRS)”, and the “Agence Natio-
nale de la Recherche” (ANR JCJC 7141) for the financial
support to this project. Dr. Karinne Miqueu and Dr. Jean-
ꢀ
Marc Sotiropoulos (Universite de Pau et des Pays de
l’Adour) are acknowledged for fruitful discussions.
The extremely mild conditions developed with this pro-
tocol allowed the participationofotheralkyl acrylates with
negligible solvent-induced transesterification byproduct.
For instance, butyl acrylate 2b could be coupled with aniline
1f with high yield (90%) without any base (Scheme 5).
The synthetic usefulness of our methodology can be
extended to the facile preparation of quinolones following
our recently developed HRC strategy (Scheme 6).19b For
instance, the Heck coupling of aniline 1d with methyl
acrylate 2a, followed by the in situ Pd-mediated reductions
of the nitro group and the double bond, furnished inter-
mediate 4 which spontaneously cyclized into the corre-
sponding quinolone 5 with an overall 80% yield.
Supporting Information Available. Experimental pro-
cedures and analytical data for all compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(21) We believe that our procedure is safer because it does not require
the use of isolated diazonium salts. Moreover, diazonium salts cannot
accumulate in solution since it is formed through the generation of
MeSO3H as observed by 1H NMR. We have performed the reaction up
to 10 mmol without any noticeable problems. However, caution is
warranted when working and handling such intermediates.
Org. Lett., Vol. 13, No. 10, 2011
2649