Access to cinnamyl derivatives from arenes and allyl esters by a biomimetic aerobic oxidative dehydrogenative coupling

Article abstract of DOI:10.1021/ol500326g

An efficient biomimetic aerobic oxidative dehydrogenative alkenylation of arenes with allyl esters is presented. The reaction proceeds under an ambient pressure of oxygen with relatively low catalyst loading of palladium acetate, employing catalytic amounts of electron-transfer mediators (ETMs). This study represents a new environmentally friendly method for the synthesis of cinnamyl derivatives.

Full text of DOI:10.1021/ol500326g

Letter
pubs.acs.org/OrgLett
Access to Cinnamyl Derivatives from Arenes and Allyl Esters by a
Biomimetic Aerobic Oxidative Dehydrogenative Coupling
Nicolas Gigant and Jan-E. Backvall*
̈
Department of Organic Chemistry, Arrhenius Laboratory, Stockholm University, SE-106 91 Stockholm, Sweden
S
* Supporting Information
ABSTRACT: An efficient biomimetic aerobic oxidative dehydro-
genative alkenylation of arenes with allyl esters is presented. The
reaction proceeds under an ambient pressure of oxygen with
relatively low catalyst loading of palladium acetate, employing
catalytic amounts of electron-transfer mediators (ETMs). This
study represents a new environmentally friendly method for the synthesis of cinnamyl derivatives.
wing to the versatility of the cinnamyl moiety as an
indispensable component of many synthetic building
Scheme 1. Competitive Pathways in the Heck Coupling
between Arenes and Allyl Esters
O
blocks, natural products, and drug candidates, its fast and easy
construction remains a continuous challenge.1 For instance,
transition-metal-catalyzed direct C−H activation offers a
powerful and economical method to create C−C bonds
without the conventional prefunctionalization.2 In particular,
direct cross-dehydrogenative coupling reactions are among the
best strategies to link two C−H bonds together, producing only
water as the molecular byproduct. Among these trans-
formations, the intermolecular coupling of arenes and alkenes,
also called “dehydrogenative Heck reaction”, first explored by
Fujiwara and Moritani,3 has attracted considerable attention
during the past decade.4 Indeed, this reaction has been used to
develop new methodologies for application in total synthesis.5
Despite recent major advancements, the “green” aspect of
these transformations is often widely affected by the use of
relatively high catalyst loading, stoichiometric, or often
overstoichiometric amounts of nonenvironmentally friendly
additives (Cu(II), Ag(I), etc.) and sometimes expensive
sacrificial oxidants other than ideal molecular oxygen. The
activation of the stable C−H bond and the catalyst regeneration
to its active form are unfortunately not favored processes. In
addition, the scope of alkenes is generally restricted to
“activated” partners, like electron-deficient olefins and styrene
derivatives. Even if allyl esters have been extensively studied as
allylic alkylation reagents to create new C−C bonds,6 their
reactivity in the Heck reaction has only recently attracted
attention due to the competing selectivities (Scheme 1).7 The
outcome of the reaction depends on: (i) Pd insertion (internal
vs terminal), (ii) selectivity in β elimination (β-H vs β-OAc),
and (iii) elimination regioselectivity (allylic vs styrenyl).
the reduced catalyst and O2 (Scheme 2).9 In this way, a low
energy pathway is created between Pd and O2, circumventing
the high energy pathway often associated with reoxidation of
Scheme 2. Aerobic Dehydrogenative Coupling (a) vs
Biomimetic Aerobic Dehydrogenative Coupling (b)
An ongoing area of research in our laboratory is the
development of green and sustainable methodologies for the
formation of new C−C bonds.8 Toward this end, we envisaged
exploration of a selective oxidative coupling between simple
arenes and allyl esters via a biomimetic approach. With this
strategy, catalytic electron-transfer mediators (ETMs), e.g., a
benzoquinone derivative and an oxygen-activating metal-
containing macrocycle, interact to decrease the barrier between
Received: January 30, 2014
Published: March 7, 2014
© 2014 American Chemical Society
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Letter
Pd by O2. In this paper, we report our results regarding the
aerobic oxidative coupling of arenes and allyl esters through a
biomimetic approach, and this new environmentally friendly
method overcomes several of the limitations mentioned above.
To investigate the Pd-catalyzed aerobic biomimetic coupling,
1,4-dimethoxybenzene (1a) and allyl acetate (2a) were chosen
as model substrates for the initial optimization of the reaction
conditions (Scheme 3).10 The seven tested parameters are
Table 1. Biomimetic Aerobic Oxidative Dehydrogenative
Coupling between Various Allyl Esters 2 and 1,4-
Dimethoxybenzene 1a
a
Scheme 3. Optimization of Reaction Conditions10
depicted in Scheme 3. Pd(OAc)2 (2.5 mol %) was the most
efficient catalyst. Screening of ETMs showed that 1,4-
benzoquinone (BQ) (10 mol %) in combination with iron
phthalocyanine Fe(Pc) (2.5 mol %) gave the best activity. More
electron-rich BQ derivatives, other metal complexes, or
different loadings did not give any improvement of the yield
of the desired product 3aa. In addition, pyridine or DMSO as
ligands did not increase the yield of the reaction and it was
found that 90 °C was the optimal temperature. A variety of
solvents were then examined, but none of them was more
efficient than acetic acid. Finally, our last efforts were focused
on the number of equivalents of arene. Whereas 5, 7, or 9 equiv
did not affect the yield, 11 or 13 equiv increased the yield to
61%. A further increase to 15 equiv decreased the yield. With
the current protocol using 13 equiv of 1a, 3aa was isolated in
61% yield with complete retention of the leaving group and
high levels of selectivity (E/Z = 20:1, L/B > 40:1).
The oxidative Heck coupling was then extended to other allyl
ester derivatives, and the results are given in Table 1. First,
different esters were tested under optimized conditions using
arene 1a (Table 1, entries 1−4). Allyl hexanoate, allyl benzoate,
and allyl cinnamate furnished products 3ab, 3ac, and 3ad,
respectively, in moderate to good yields. The selectivity for the
attack of the aryl group at the terminal position was high. The
effect of the substitution on the allyl moiety was next examined.
Allyl esters bearing aliphatic chains next to the oxygen atom
were also good alkenylating partners, giving 3ae−ag with high
selectivities (Table 1, entries 5−7). Surprisingly, a phenyl
substituent next to the oxygen reversed the E/Z ratio in favor of
the Z isomer of 3ah (Table 1, entry 8). For allyl acetate 2i, the
L/B ratio was affected (3:1) even if a significant preference for
the desired cinnamyl product 3ai was preserved (Table 1, entry
9). Furthermore, when cinnamyl acetate was subjected to our
experimental conditions, a mixture of linear and branched
products 3aj was isolated in high yield (Table 1, entry 10).
a
Unless otherwise noted, the reactions were carried out at 90 °C using
2 (0.30 mmol), 1a (13 equiv), Pd(OAc)2 (2.5 mol %), BQ (10 mol
%), and Fe(Pc) (2.5 mol %) in AcOH (1 mL) for 24 h under O2
(balloon). Isolated yield. E/Z and L/B ratios determined using H
NMR analysis of isolated mixtures. Reaction performed in a mixture
of AcOH/dioxane (0.5 mL/0.5 mL).
b
c
1
d
Steric effects certainly play an important role in this coupling
and it seems reasonable to expect that the phenyl moiety favors
the external Pd insertion (Scheme 1).
After evaluating the scope with allyl esters, we next applied
this catalytic system to various arenes to demonstrate the
efficiency and scope of the present method (Table 2).
Gratifyingly, it should be noted that all products were obtained
in high levels of selectivity (E/Z and L/B ratios). A series of
1,4-disubstituted arenes were coupled to produce the desired
scaffolds in moderate to good yields. Symmetrical arenes gave a
single isomer, and the coupling was efficient with only a catalyst
loading of 2.5 mol % for electron-rich arenes 1a,b (Table 2,
entries 1 and 2). Electron-neutral or -poor arenes 1c−e were
less reactive and required an increase to 5 mol % of Pd(OAc)2
(Table 2, entries 3−5). We presume that the lower reactivity is
due to the decreased nucleophilicity of the arene. Interestingly,
a wide range of p-functionalized anisole derivatives underwent
the coupling smoothly: either methyl, chloro, bromo, or fluoro
moieties were tolerated, giving 3fa−ia as a mixture of isomers
in satisfying yields (Table 2, entries 6−9). Additionally, the
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Letter
a
Table 2. Biomimetic Aerobic Oxidative Dehydrogenative Coupling between Allyl Acetate 2a and Various Arenes 1
a
b
c
For reaction conditions, see Table 1. Isolated overall yields of the E/Z and B isomers. Product ratios determined by 1H NMR analysis of isolated
d
e
f
g
h
mixtures. Pd(OAc)2 (2.5 mol %). Pd(OAc)2 (5 mol %). Reaction performed at 80 °C. Pd(OAc)2 (3.75 mol %). Pd(OAc)2 (1.25 mol %).
reactivity of 1,2-difunctionalized arenes was also investigated.
When o-xylene was allowed to react with allyl acetate, the
desired cinnamyl derivative 3ja was isolated in good yield,
whereas o-dichlorobenzene 1k was less reactive (Table 2,
entries 10 and 11). Under similar reaction conditions, other
simple bicyclic substrates such as naphtalene, tetralin, or indane
reacted efficiently with allyl acetate, forming the corresponding
derivatives 3la−na with moderate selectivities in good yields
(Table 2, entries 12−14). Importantly, a very low palladium
loading (1.25 mol %) was successfully employed with 1,3-
benzodioxole 1o as coupling partner, and surprisingly, the
sterically more hindered position was favored (Table 2, entry
15). Monosubstituted arenes 1p and 1q bearing an electron-
donating group gave the desired alkenylated anisole 3pa and
phenetole 3qa, respectively, in good yields in a similar ratio of
o/m/p regioisomers (Table 2, entries 16 and 17). Both
chlorobenzene 1r and bromobenzene 1s were tolerated,
providing valuable handles for further functionalization
(Table 2, entries 18 and 19).
performed. The corresponding functionalized analogue 3ak
was produced in reasonable yield (47%) (Scheme 4).
Scheme 4. Biomimetic Late-Stage Arylation of Butafenacil
As documented previously, an electrophilic palladation
pathway can be envisaged in the oxidative coupling between
1 and 2.4,5b In order to confirm this mechanistic scenario,
isotope effect studies were carried out. A significant kinetic
isotopic effect (KIE) of 4.2 was measured by comparing the
initial rates for two parallel reactions between 1d or 1d-d6 and
allyl acetate 2a, revealing that the C−H bond cleavage of the
aromatic ring is involved in the rate-determining step of the
biomimetic coupling (Scheme 5).10 The high selectivity in favor
of the cinnamyl derivative can be explained by a strong
Late-stage diversification of biologically active molecules is a
unique method to easily elaborate analogous compounds with
improved pharmacologic activity or for the detection of
structure−activity relationships (SAR).2c To this end, a late-
stage arylation of butafenacil, which is a commercial herbicide
mainly providing rapid knockdown of grass weeds, was
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Scheme 5. Evaluation of Deuterium Isotope Effect
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(Scheme 2b). The catalyst is simply regenerated in its active
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molecular oxygen at atmospheric pressure to finally complete
the catalytic cycle.
In conclusion, a selective biomimetic aerobic oxidative
dehydrogenative coupling between simple arenes and allyl
esters yielding cinnamyl derivatives has been developed. The
major advantage of this method is that molecular oxygen at
ambient pressure can be used as the oxidant. The aerobic
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ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures and full characterization details
including 1H and 13C NMR and HRMS. This material is
available free of charge via the Internet at http://pubs.acs.org.
(8) (a) Volla, C. M. R.; Backvall, J.-E. Angew. Chem., Int. Ed. 2013, 52,
̈
14209−14213. (b) Gigant, N.; Backvall, J.-E. Chem.Eur. J. 2013, 19,
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10799−10803. (c) Endo, Y.; Backvall, J.-E. Chem.Eur. J. 2012, 18,
̈
AUTHOR INFORMATION
Corresponding Author
■
13609−13613. (d) Babu, B. P.; Endo, Y.; Backvall, J.-E. Chem.Eur. J.
̈
2012, 18, 11524−11527. (e) Endo, Y.; Backvall, J.-E. Chem.Eur. J.
̈
́
*E-mail: jeb@organ.su.se.
Notes
2011, 17, 12596−12601. (f) Persson, A. K. Å.; Backvall, J.-E. Angew.
̈
Chem., Int. Ed. 2010, 49, 4624−4627. (g) Piera, J.; Persson, A.;
Caldentey, X.; Backvall, J.-E. J. Am. Chem. Soc. 2007, 129, 14120−
̈
The authors declare no competing financial interest.
14121.
(9) For a recent review, see: Piera, J.; Backvall, J.-E. Angew. Chem., Int.
Ed. 2008, 47, 3506−3523.
(10) See the Supporting Information for more details.
̈
ACKNOWLEDGMENTS
■
Financial support from the European Research Council (ERC
AdG 247014), The Swedish Research Council, and The Knut
and Alice Wallenberg Foundation is gratefully acknowledged.
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