Ring-Opening Ortho-C-H Allylation of Benzoic Acids with Vinylcyclopropanes: Merging Catalytic C-H and C-C Activation Concepts

Article abstract of DOI:10.1021/acs.orglett.9b02393

A Ru-catalyzed selective and atom-economic ortho-C-H allylation of aromatic acids with vinylcyclopropanes is reported. The reaction proceeds with selective cleavage of both a C-H and a C-C bond. A wide range of allylarenes were synthesized in high yields

Full text of DOI:10.1021/acs.orglett.9b02393

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Ring-Opening Ortho-C−H Allylation of Benzoic Acids with
Vinylcyclopropanes: Merging Catalytic C−H and C−C Activation
Concepts
Zhiyong Hu, Xiao-Qiang Hu, Guodong Zhang, and Lukas J. Gooßen*
Lehrstuhl fur Organische Chemie I, Ruhr-Universitat Bochum, Universitatsstrasse 150, 44801 Bochum, Germany
̈
̈ ̈
S
* Supporting Information
ABSTRACT: A Ru-catalyzed selective and atom-economic ortho-C−
H allylation of aromatic acids with vinylcyclopropanes is reported. The
reaction proceeds with selective cleavage of both a C−H and a C−C
bond. A wide range of allylarenes were synthesized in high yields and
stereoselectivities. The vinylcyclopropane substrates can optionally be
generated in situ from a diazo compound and 1,3-butadiene. Concise
syntheses of isocoumarin and 3,4-dihydroisocoumarin derivatives underline the synthetic utility of the reaction.
ransition-metal-catalyzed directed C−H functionalization
Thas become a key technology for the regioselective
construction of complex molecules from simple precursors.1
Initially, the regiospecificity of the transformation was often
enforced by strongly coordinating, complex directing groups.2
In the past decade, new catalyst generations have permitted the
use of abundant functionalities, such as carboxylates, as
directing groups, with key contributions made by Yu,3
Miura,4 Larrosa,5 Su,6 Ackermann,7 our group,8 and others.9
The main advantage of carboxylate directing groups is that
they are ubiquitously available and can either be tracelessly
removed or utilized as leaving groups in decarboxylative
couplings.10
We have recently found that Ru catalyst systems strongly
facilitate C−X over C−H elimination pathways and, thus,
permit the selective ortho-allylation of benzoic acids with allyl
sources of remarkably low intrinsic reactivities, such as allyl
alcohols and even amines.8b,c Intrigued by the reactivity
displayed by this catalyst, we went on to explore its application
to allyl sources with carbon-based leaving groups (Schemes 1
and 2).
Scheme 2. Mechanistic Blueprint
In this context, the Ru-catalyzed ortho-hydroarylations11 of
benzoic acids have proven to be a versatile entry point to
organoruthenium intermediates that can enter an array of
diverse reaction pathways (Scheme 1). Potential products
include alkyl- and vinylarenes (a, b)7a,12 and alkenyl- and
alkylcarboxylates (c, d).13
Scheme 1. Ru-Catalyzed Hydroarylation Processes with
Carboxylates
The selective activation of inert C−C bonds is challenging
due to their high bond dissociation energy of ca. 90 kcal/
mol.14 In the context of low-valent transition-metal-catalyzed
allylations of preformed nucleophiles, the ring strain of
vinylcyclopropanes has successfully been utilized to facilitate
the cleavage of a C−C bond, leading to the formation of
allylmetal intermediates.15 However, there are very few
reactions that combine catalytic C−H functionalizations with
C−C bond activation steps,16 and they all involve high
Received: July 11, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b02393
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
molecular-weight, nitrogen-based directing groups,17 which
often need to be preinstalled and later removed in additional
reaction steps. We reasoned that our ruthenium-based system
for carboxylate-directed C−H activation should display a
similar reactivity toward vinylcyclopropanes as observed, e.g.,
for allyl alcohols (Scheme 2).
Thus, a benzoic acid 1 should react with a ruthenium
complex to form a ruthenacycle (B), which would coordinate
the C−C double bond of 2, followed by carbometalation to
give D. This intermediate is now ideally set up for a concerted
C−C bond-cleavage process in which the leaving group is
transferred to Ru.17f,i The product is liberated from the
resulting species E by protonation/exchange with the benzoic
acid substrate.
temperature from 70 to 55 °C (entry 16), and increasing the
amount of catalyst to 4 mol % (entry 17). A further control
experiment with p-methylbenzoic acid (1k) bearing no ortho
substituents revealed that no diallylation occurred even when
increasing the excess of 2a to 2.5 equiv.
Under these optimized conditions (Table 1, entry 17),
various aromatic carboxylic acids were successfully allylated
with the model substrate diisopropyl 2-vinylcyclopropane-1,1-
dicarboxylate 2a in good yields and high E/Z selectivities
(Scheme 3). Notably, not only ortho-substituted benzoates but
a
Scheme 3. Substrate Scope
In order to probe the viability of this reaction concept, we
chose 2-methylbenzoic acid 1a and diisopropyl 2-vinyl-
cyclopropane-1,1-dicarboxylate 2a as model substrates (Table
1). Gas chromatographic analysis of the reaction mixtures was
a
Table 1. Optimization of the Allylation Reaction
b
entry
solvent
base
yield (%)
E/Z ratio
1
2
3
4
5
6
7
TCE
K3PO4
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
5
46
15
20
26
7:1
4.5:1
3:1
5:1
2:1
MeCN
DCE
DME
DMF
H2O
trace
32
iPrOH
3.5:1
5:1
8
TFE
Na2CO3
20
9
TCE
Na2CO3
15
8:1
10
11
12
13
14
15
16
17
HFIP
HFIP
HFIP
HFIP
HFIP
HFIP
HFIP
HFIP
Na2CO3
K2CO3
Cs2CO3
K3PO4
K2CO3 + Na2CO3
K2CO3 + Na2CO3
K2CO3 + Na2CO3
K2CO3 + Na2CO3
67
46
35
50
59
68
76
91
7.5:1
20:1
15:1
14:1
16:1
16:1
15:1
16:1
c
c d
,
c de
,
,
a
Conditions: 0.2 mmol of 1a, 0.3 mmol of 2a, 2.5 mol % of [Ru(p-
b
cymene)Cl2]2, 1 equiv of base, 1 mL of solvent, 70 °C, 24 h. Yields
determined by GC using methyl laurate as internal standard; E/Z
c
1
ratios determined by H NMR. With 50 mg of powdered 4 Å MS.
d
e
55 °C. 4 mol % of [Ru]. K2CO3 (1.3 equiv) + Na2CO3 (0.3 equiv).
HFIP = hexafluoro-2-propanol. TFE = 2,2,2-trifluoroethanol. TCE =
2,2,2-trichloroethanol.
a
Conditions: 1 (0.5 mmol), 2 (0.75 mmol), [Ru(p-cymene)Cl2]2 (4
mol %), K2CO3 (0.65 mmol), Na2CO3 (0.15 mmol), 4 Å MS (50 mg)
in HFIP (2 mL) at 55 °C under Ar; isolated yields of corresponding
made simpler by converting the products in situ to the methyl
esters. Using [Ru(p-cymene)Cl2]2 as a catalyst under the
conditions optimized for C−H allylations with allyl alcohol
substrates, the desired product was formed in encouraging
quantities (entry 1). The solvent system played a key role in
yield and E/Z selectivity (entries 2−10). The best results were
obtained using hexafluoro-2-propanol (HFIP). The reaction
outcome was strongly influenced also by the base (entries 10−
13). The optimal combination of conversion and stereo-
selectivity was obtained with a 4:1 mixture of potassium and
sodium carbonate. Further step-ups in the yield were achieved
by employing 4 Å MS as an additive (entry 15), lowering the
b
methyl esters. Based on 0.2 mmol.
also meta-, para-, and unsubstituted derivatives were selectively
monoallylated. Halogen substituents, including even iodo
groups, are left unchanged, so that transformation is
orthogonal to most transition-metal-catalyzed processes. The
reaction also tolerates, e.g., ester, ether, or keto groups.
Heterocyclic carboxylates were also smoothly converted, albeit
with lower stereoselectivity (3ta, 3ua). Starting from
terephthalic acid, the diallylation product (3va) was obtained
in 20% yield. However, the current catalyst system does not
B
DOI: 10.1021/acs.orglett.9b02393
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
allow the analogous conversion of acrylic acid derivatives such
as 1-cyclohexene-1-carboxylic acid 1w.
deuteration was observed, confirming that the C−H activation
step is reversible (Scheme 6a). When the allylation was carried
Variations of the vinylcyclopropane coupling partner were
also investigated. At least two activating groups were found to
be required. The reaction is suppressed by alkyl substituents
and is senstitive to steric crowding at the vinylcyclopropane
substructure. Whereas smaller ester groups gave good yields
but only moderate stereoselectivity in favor of the E products,
the latter were obtained almost exclusively when starting from
bulky tert-butyl esters, albeit in modest yields (3ab, 3ac, 3ad).
Vinylcyclopropanes bearing ketone (2e, 2f), cyano (2g), and
sulfonyl groups (2h) were smoothly converted, but the
diketone 2m was found to be unreactive (see the SI). Strained
heterocycles such as 3,4-epoxy-1-butene (2n) and vinyl
aziridine (2o) did not give the desired allylation products
(Scheme S1).
Scheme 6. Mechanistic Insights
In the small-scale reactions above, the products were isolated
by column chromatography as their methyl esters following in
situ esterification. However, it is also possible to isolate the
carboxylic acids themselves. This was demonstrated by the
gram-scale (4 mmol) synthesis of allylation product 3aa′
yielding 85% of the free acid.
We next probed whether the synthesis of the vinyl-
cyclopropane substrates from widely available starting
materials could be performed as a one-pot process with the
C−H allylation. To our delight, the Rh-catalyzed cyclo-
propanation of 1,3-butadiene with diazo ester 2a′ turned out to
be mutually compatible with the Ru-catalyzed allylation. Thus,
the allylbenzoic acid 3aa was synthesized in respectable yield in
one pot from o-toluic acid (1a), diazo ester 2a′, and a toluene
solution of butadiene (Scheme 4).18
out in the presence of d2-HFIP, deuterium uptake in the α-
postion of dicarboxylate groups was observed, pointing toward
a protodemetalation rather than a hydride-transfer mechanism
(Scheme 6b). Taken together with the high kinetic isotope
effect, one can conclude that C−H cleavage is rate-
determining, whereas the hydroarylation is much faster
(Scheme 6c). All of these findings are in good agreement
with the mechanism shown in Scheme 2.
In conclusion, simple p-cymene ruthenium catalyst allows
the ortho-C−H allylation of aromatic carboxylates with
vinylcyclopropanes under mild, redox-neutral conditions.
This use of a carbon-based leaving group represents a major
advance in the field of carboxylate-directed reactions. The new
allylation has considerable synthetic potential, particularly due
to its tolerance of halo functionalities, which makes it
orthogonal to most catalytic C−C and C−heteroatom bond-
forming reactions. Moreover, it can be combined with an up
front diene cyclopropanation or with follow-up reactions such
as oxidative lactonizations.
Scheme 4. One-Pot for Cyclization, C−H Activation, and
Ring-Opening
ASSOCIATED CONTENT
* Supporting Information
■
S
The allylation reaction can also be combined with follow-up
steps. For example, the 3,4-dihydroisocoumarin derivative 4
was obtained in 61% yield via allylation followed by an
epoxidation/ring-opening cascade (Scheme 5a). Allylation
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b02393.
Experimental procedures, full analysis data for new
compounds, and NMR spectra (PDF)
Scheme 5. In Situ Product Derivatization
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: lukas.goossen@rub.de.
ORCID
Lukas J. Gooßen: 0000-0002-2547-3037
Notes
The authors declare no competing financial interest.
followed by Pd-catalyzed intramolecular aerobic cyclization
led to the isocoumarin 5 (Scheme 5b). Both of these bicyclic
product classes are of interest due to their antibacterial,
antifungal, anti-inflammatory, antioxidant, and anticancer
activities.19
The mechanism of the allylation reaction was investigated by
deuterium-labeling experiments. Upon stirring the benzoic acid
1a in the presence of catalyst and base in d2-HFIP, rapid ortho-
ACKNOWLEDGMENTS
■
Funded by the Deutsche Forschungsgemeinschaft (DFG,
German Research Foundation) under Germany’s Excellence
Strategy, EXC-2033, Projektnummer 390677874, SFB-TRR 88
“3MET”, and GO 853/12-1, and BMBF and the state of NRW
(Center of Solvation Science “ZEMOS”). We thank
C
DOI: 10.1021/acs.orglett.9b02393
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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UMICORE for donating chemicals and the CSC for
fellowships to G.Z. and Z.H.
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