Palladium-catalyzed salt-free double decarboxylative aryl allylation

Article abstract of DOI:10.1039/c8ob01806e

This report describes a palladium-catalyzed decarboxylative aryl allylation between unactivated benzoic acids and allylic carbonates. This transformation successfully couples a variety of carbonates and benzoic acids in good yield (up to 94%) using 1 mol% palladium. This salt free allyl-arylation proceeds without added base, copper, or silver. The only stoichiometric byproducts are carbon dioxide and tert-butanol.

Full text of DOI:10.1039/c8ob01806e

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Takeharu Haino et al.
Solvent-induced emission of organogels based on tris(phenylisoxazolyl)
benzene
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Palladium-Catalyzed Salt-Free Double Decarboxylative Aryl
Allylation
Received 00th January 20xx,
Accepted 00th January 20xx
Ryan A. Daley and Joseph J. Topczewski*
DOI: 10.1039/x0xx00000x
www.rsc.org/
halides, aryl tosylates and alkenes,20,21 which is in contrast to the
This report describes a palladium-catalyzed decarboxylative aryl
allylation between unactivated benzoic acids and allylic
carbonates. This transformation successfully couples a variety of
carbonates and benzoic acids in good yield (up to 94%) using 1
mol% palladium. This salt free allyl-arylation proceeds without
added base, copper, or silver. The only stoichiometric byproducts
are carbon dioxide and tert-butanol.
broad scope of alkyl decarboxylation reacitons.22 A few successful
allylation reactions have been reported. In 2011, Liu reported the
decarboxylative allylation of electron rich benzoic acids with a
mixture of catalytic palladium, catalytic copper, and stoichiometric
silver (Scheme 1a).23 The reaction relied on large quantities of silver
for catalytic turnover and was not amenable to using allylic
acetates, which underwent Heck coupling. In 2014, Jana24 and
Gooßen15 independently reported intramolecular decarboxylative
allylations of preformed esters (Scheme 1b and 1c respectively).
Jana attempted the coupling with free benzoic acids, but was
Traditional palladium catalyzed cross-coupling reactions
enable the synthesis of natural products, agrochemicals, and
pharmacueticals.1,2 Classically, these transformations are limited by
the use of stoichiometric organometallic nucleophiles, which can be
expensive to prepare and are often unstable. Additionally, such
transformations often require insoluble inorganic bases or additives
to activate the catalyst for transmetalation.3 The products are
typically purified from excess base or other stoichiometric salts via
liquid-liquid extraction. Solvents account for 80-90% of the mass
used in the pharmaceutical industry,4 of which a sizable percentage
is used during extractions. Water, used primary for salt removal,
accounts for ~20% of the mass used in synthesis even after process
optimization.5 As such, the use of preformed metal nucleophiles
and inorganic bases generates a substantial amount of waste.
Developing catalytic methods that do not require these additives
and that can proceed without salt formation are therefore
advantageous.
unable
to
attain
selectivity
for
allylation
over
protodecarboxylation.24
a) Liu 2011:
O
[Pd], [Cu]
[Ag]
OH
+
X
-CO2
R
R
b) Jana 2014:
NO2
O
NO2
[Pd], [Ag]
-CO2
O
R'
R'
R'
R
R
c) Gooßen 2014:
O
An alternative route to access aryl-metal intermediates
[Pd]
O
R'
Ar
for cross-coupling is through the decarboxylation of benzoic acids.
Decarboxylation has emerged as an exciting alternative to both
traditional cross-coupling and C-H activation because it uses simple
-CO2
R
R
R
d) This Work:
and readily available benzoic acids and is highly site-selective.6,7
A
O
OBoc
Ar
variety of transition metals such as copper,8,9 silver,10,11 gold,12,13
and palladium14–19 are competent for the decarboxylation of
benzoic acids. Many protocols however are impractical because
they use multiple metal sources, additional additives, and/or pre-
activated benzoic acids (carboxylate salts or activated esters).
In aryl-decarboxylative coupling, the identity of the
[Pd]
+
OH
-2CO2
-t-BuOH
R
Scheme 1 Palladium-Catalyzed Decarboxylative Allylations.
Herein, we report method for the intermolecular
a
decarboxylative allylation between free benzoic acids and allyl-tert-
butyl-carbonates (Scheme 1d). This reaction likely generates an
equivalent of tert-butoxide in situ, which can subsequently
deprotonate the benzoic acid. As such, no exogenous base is
required. The stoichiometric byproducts, carbon dioxide and tert-
butanol, are volatile, which obviates the need for an aqueous
extraction or additional solvent.
electrophilic coupling partner has been mostly limited to aryl
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Our investigation into decarboxylative allylation began with the However, our current understanding is consistent with the general
coupling between 2,6-difluorobenzoic acid (1a), which readily mechanism shown (Scheme 2). Ligand exchange on the pre-
decarboxylates with palladium,15 and carbonate 2a, a preferred catalysts to forms a ligated palladium (0). Oxidative addition with
substrate for allylation. Conditions with 5 mol% Pd2dba3, 10 mol% the allylic carbonate could generate a π-allyl palladium (II) complex
BINAP, in anhydrous 1,4-dioxane, at 140 °C provided a modest yield (Scheme 2i). The initial complex could lose CO2 to generate tert-
of product 3a (table 1, entry 1). In our hands, using Pd2dba3 as a butoxide, which would facilitate ligand exchange with the benzoic
palladium source afforded variable results. The precatalyst Pd2dba3 acid (Scheme 2ii). A second decarboxylation from the palladium
is known to form nanoparticles of Pd,25 and this could be the cause carboxylate would generate a new palladium (II) aryl complex
of the observed irreproducibility. Changing the pre-catalyst to the (Scheme 2iii). Reductive elimination would afford the product and
palladium(II) complex Pd1 improved the yield to 68% (table 1, entry regenerate palladium (0) (Scheme 2iv). Several by-products of this
2), while the use of precatalysts Pd2 and Pd3 led to a significant reaction where characterized throughout this work and
decrease in yield (table 1, entries 3-4). Furthermore, using complex description is included (see ESI for details).
Pd1 as the palladium source provided more reproducible outcomes.
The reaction was not improved by modifying the bidentate ligand
(table 1, entries 5-8) or by using a monodentate ligand (table 1,
entries 9-11). Using less ligand was tolerated (table 1, entry 12). As
anticipated, the reaction was inhibited by excess BINAP (table 1,
entry 13) as the palladium likely becomes coordinately saturated.
Lowering the catalyst loading to 5 mol% Pd and then to 1 mol% Pd
increased the yield to 86% by improving the selectivity of the
reaction (table 1, entries 14, 15) These conditions are the first
intermolecular allylation that occurs with a low loading of a single
metal and use the free carboxylic acid.
a
Table 1 Optimization of the decarboxylative allylation reaction. a
Scheme 2 Proposed Mechanism for Allylation.
With the optimized conditions identified, we explored the
substrate scope of the carbonate coupling partner using 2,6-
difluorobenzoic acid (table 2). Both branched carbonates (2a, 2b)
and linear carbonates (2a’, 2b’) gave comparable yields of products
3a and 3b respectively. Either carbonate presumably generates the
same π-allyl-Pd intermediate. The reaction worked well with
carbonates containing a fluorine atom in the para (2c), meta (2), or
ortho (2e) position. Napthyl carbonate (2f) as well as carbonates
containing additional remote alkyl or aryl groups (2g, 2h, and 2k)
readily underwent the allylation in good yield. Both electron rich
carbonates (2i, and 2m) and electron deficient carbonate 2j were
compatible with the reaction. Electron rich carbonates (2i and 2m)
and an electron deficient carbonate (2j) underwent the reaction at
significantly different rates (18h vs 5 days). Carbonates with ortho-
groups (2L, 2m) were tolerated. Unfortunately,
a carbonate
containing a cyclic alkene (2n) failed to form product under the
reaction conditions.
The benzoic acid scope was more limited than the scope of
allylic carbonates. Like other palladium catalyzed decarboxylations,
two ortho-substituents are required for reactivity and to prevent
competitive directed C-H activation. Benzoic acids with additional
para- or meta-fluoro substituents (3o and 3p) provided a good yield
under the reaction conditions. However, the yield for the
decarboxylation of pentaflourobenzoic acid (3q) was poor due to
uncontrolled protodecarboxylation. The addition of an aryl chloro
a Reaction conditions: benzoic acid (63 μmol), carbonate (95 μmol), biphenyl
standard (16 μmol), [Pd] (0.6 - 6 μmol, 1 - 10 mol %), ligand (0.6 - 6 μmol, 1 -
10 mol %), 1,4-dioxane (0.32 mL), under nitrogen, at 140 °C for 24h. b Yields
were determined by calibrated GC−FID analysis. Reacꢀons were carried out
in triplicate, and the average value is reported.
We propose a mechanism for this transformation that is based substituent significantly decreased the yield (3r), likely caused by
on prior work regarding palladium catalysed decarboxylation
reactions (Scheme 2).26,27 Our reaction was not inhibited by the
addition of TEMPO or BHT, which supports a two-electron pathway
(see ESI for details). Without a more detailed kinetic analysis it is
difficult to assign the exact sequence of events or ancillary ligands.
competitive oxidative addition of palladium into the carbon-
chlorine bond. The addition of electron donating groups (3s, 3t, 3u,
and 3v)
2 | J. Name., 2012, 00, 1-3
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Table 2 Scope of the carbonate coupling partner for the decarboxylative allylation.
a Reaction conditions: benzoic acid (430 μmol), carbonate (640 μmol), Pd1 (4.3 μmol, 1 mol %), BINAP (4.3 μmol, 1 mol %), 1,4-dioxane (2.1 mL), under
nitrogen, at 140 °C for 24h. b Yields are of isolated and purified material. Values reported are the average of duplicate, or triplicate trials. c Reaction run for
18h. d Reaction run for 5 days.
free approach to decarboxylation will be reported in due
course.
required increased temperatures, but still provided an acceptable
yield of the product. Either or both of the two ortho-fluorines could
be replaced with methoxy groups (3w and 3x).
Conflicts of interest
We declare no conflicts of interest.
Conclusions
In conclusion, we report the first salt-free intermolecular
decarboxylative allylation reaction between free benzoic acids
Acknowledgements
Alanna Hildebrandt is thanked for helping with starting
material synthesis. Financial support was provided by the
University of Minnesota.
and allylic tert-butyl-carbonates. The combination of
precatalyst Pd1 with BINAP was found to promote the reaction
at
successfully applied to
1
mol% catalyst loading. The transformation was
variety carbonates and 2,6-
a
disubstituted benzoic acids. Further applications of our salt
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a Reaction conditions: benzoic acid (430 μmol), carbonate (640 μmol), Pd1
(4.3 μmol, 1 mol %), BINAP (4.3 μmol, 1 mol %), 1,4-dioxane (2.1 mL), under
b
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e
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180 °C for 48h.
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