Regiospecific ortho-C?H Allylation of Benzoic Acids

Article abstract of DOI:10.1002/anie.201712520

A carboxylate-directed ortho-C?H functionalization has been developed and it allows the regiospecific introduction of allyl residues to benzoic acids. In the presence of a [Ru(p-cymene)Cl₂]₂ and K₃PO₄, benzoic acids react with allyl acetates at only 50 °C to give the corresponding ortho-allylbenzoic acids. The protocol is generally applicable to both electron-rich and electron-poor benzoic acids in combination with linear and branched allyl acetates. The products can be further functionalized in situ, for example, by double-bond migration, lactonization, or decarboxylation.

Full text of DOI:10.1002/anie.201712520

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Accepted Article
Title: Regiospecific ortho-C-H Allylation of Benzoic Acids
Authors: Stefania Trita, Agostino Biafora, Martin Pichette-Drapeau,
Philip Weber, and Lukas J Goossen
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201712520
Angew. Chem. 10.1002/ange.201712520
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10.1002/anie.201712520
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Regiospecific ortho-CH Allylation of Benzoic Acids
A. Stefania Trita,[a] Agostino Biafora,[b] Martin Pichette-Drapeau,[a] Philip Weber,[a] and Lukas J.
Gooßen*[a]
Abstract: A carboxylate-directed ortho-C–H functionalization has
been developed that allows the regiospecific introduction of allyl
residues to benzoic acids. In the presence of a [Ru(p-cymene)Cl2]2
catalyst and K3PO4, benzoic acids react with allyl acetates at only
50 °C to give the corresponding ortho-allylbenzoic acids. The protocol
is generally applicable to both electron-rich and electron-poor benzoic
acids in combination with linear and branched allyl acetates. The
products can further be functionalized in situ, e.g. by double-bond
migration, lactonization, or decarboxylation.
Currently, the focus in the field of C–H activation is shifting
towards the use of simple, abundant functionalities as directing
groups. In this context, carboxylates have many advantages.
Benzoic acids are widely available at low cost and in great
structural
diversity.
Following
regiospecific
ortho-CH
functionalization, the carboxylate moiety can be tracelessly
removed via protodecarboxylation,[14] or used as anchor point for
decarboxylative cross-couplings.[15] However, the weak
coordinating ability compared to (bidentate) nitrogen donors
multiplies the hurdles encountered in catalytic reaction
development.[16] Still, efficient protocols have been disclosed for
Allylarenes are common structural motifs widely encountered
in the flavor and fragrance industry, pharmaceuticals, natural
products, and functional materials (Figure 1).[1] Traditionally,
allylarenes are accessed via Friedel-Crafts allylations[2] or various
cross-couplings of electrophiles with organometallic reagents.[3]
However, these approaches either suffer from poor
regioselectivity or require prefunctionalized arene derivatives, and
generate substantial amounts of salt waste.
carboxylate-directed
ortho-CH
arylations,[17]
alkenylations,[18]acylations,[19] alkoxylations,[20] halogenations,[21]
and CN bond formations,[22] often using Pd, Rh, Ir, or Ru
catalysts.
Ru-1
base
alprenolol
(beta blocking agent)
olopatadine
(antihistamine)
mycophenolic acid
(graft-versus-host disease)
1
AcOH
Figure 1 Selected examples of allyl-containing bioactive molecules.
3
H+
-O elimination
A
These limitations may be overcome by using catalytic C–H
allylations. Only
a few, specialized substrates such as
polyfluorinated arenes intrinsically give high stereoselectivities in
direct allylations.[4] In most cases, regiospecificity of the allylation
process is ensured by strongly coordinating nitrogen-based
directing groups[5] in combination with Ir,[6] Rh,[7] Ru,[8] Co,[9] Ni,[10]
Fe,[11]or Mn catalysts.[12] The inherent drawback of these first-
generation directing groups is that their installation and removal
are labor- and waste-intensive.[13]
2
C
migratory insertion
B
Scheme 1. Mechanistic blueprint for a carboxylate-directed ortho-C-H allylation
of arenes.
Catalytic ortho-C–H allylations of benzoates are equally
desirable transformations, but even harder to accomplish
(Scheme 1). The initiating step in directed C–H functionalizations
would have to be an ortho-C–H activation of the benzoate, and
allyl electrophiles tend to interfere with this step. They may
[a]
[b]
A. S. Trita, Dr. M. Pichette-Drapeau, P. M. Weber, Prof. Dr. L. J.
Gooßen
Fakultät Chemie und Biochemie
Ruhr Universität Bochum
Universitätsstr. 150, 44801 Bochum (Germany)
E-mail: lukas.goossen@rub.de
A. Biafora
FB Chemie-Organische Chemie
TU Kaiserslautern
esterify the benzoates,[23] complicating formation of
a
cyclometallated species A. Many metals preferentially undergo
oxidative insertion into allyl–X bonds, leading to intermediates
that are inactive towards C–H insertion.[24] We are aware of only
one catalytic CH allylation of benzoates. Takai et al. reported a
Re-catalyzed rearrangement of allyl benzoates to ortho-
Erwin-Schrödinger-Str. Geb. 54, 67663 Kaiserslautern (Germany)
Supporting information for this article is given via a link at the end of
the document
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10.1002/anie.201712520
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allylbenzoic acids via intramolecular C–H functionalization.[25]
This pioneering contribution has several drawbacks, such as the
necessity to pre-form the allyl benzoate and to use additional allyl
acetate, the relatively high reaction temperatures, and an in situ
saponification step.
TCE = 2,2,2-trichloroethanol. HFIP = hexafluoro-2-propanol. AcOH = acetic
acid.
In order to probe the feasibility of the desired ruthenium-
catalyzed ortho-allylation of benzoates, we chose the reaction of
2-fluorobenzoic acid (1a) with allyl acetate (2a) as a model and
investigated various catalysts and conditions (Table 1).
In the course of our work on carboxylate-directed
hydroarylations,[18d,g] we noticed the remarkable ease with which
ruthenium inserts into an ortho-C–H bond with formation of
ruthenacycles, and the preference of this metal for additions
across multiple bonds over oxidative insertion processes. We
reasoned that this reactivity might support the catalytic cycle for
carboxylate allylations sketched out in Scheme 1. The reaction is
initiated with a carboxylate-directed, base-assisted ortho-C–H
activation of the benzoate. If the resulting ruthenacycle A adds
across the double bond of an allyl acetate, an alkylruthenium
species (C) will form with Ru in-position to the acetate. The
challenge is now to open up a new pathway that liberates the
desired allylated benzoate via elimination of ruthenium acetate,
and to retard classical pathways such as Heck-type reaction via
β-hydride elimination, or hydroarylation via reductive C–H
elimination. We saw a good chance that this could be achieved,
since reductive carboxylate eliminations have literature precedent,
e.g. in allylations of benzamides or aromatic ketoximes catalyzed
by Rh or Ru.[7a,c, 8c,e]
We were delighted to find that the desired product forms in
encouraging yields already at 50°C using inexpensive [Ru(p-
cymene)Cl2]2 (Ru-1) as the catalyst and K2CO3 as the base in
NMP (Entry 1). Systematic screening of the reaction conditions
revealed that the solvent system is the most critical reaction
parameter.[26] Most aprotic solvents, both polar and non-polar,
were ineffective (entries 2 and 3). However, protic, alcoholic
solvents greatly increased the yields. The best results were
obtained with 2,2,2-trichloroethanol (pKa = 12.24[27]) (entry 4).
Less acidic ethanol (pKa
=
15.9[28]
)
and more acidic
hexafluoroisopropanol (pKa = 9.3[28]) or acetic acid (pKa = 4.76[28]
)
gave lower conversion (entries 5-7). 2,2,2-trifluoroethanol (pKa =
12.37[27]) was effective, but led to partial isomerization to 4aa
(entry 8). The reaction is also sensitive to the nature and amount
of base. The best results were obtained when the medium was
buffered with 0.7 equivalents of potassium phosphate (entries 9-
11). The reaction is best performed in concentrated solution (entry
12). The reaction temperature of 50 °C is remarkably low for a C–
Table 1. Optimization of the ortho allylation conditions.[a]
H
functionalization process. Under the optimized reaction
conditions, allyl benzoate 7a was not observed. At higher
temperatures, the thermodynamically favored isomerization
product (4aa) starts to form in significant amounts (entry 13). By
performing the reaction at 100 °C in TFE, this can be exploited to
access the vinylic product 4aa in good yield and an E/Z ratio of
30:1 (entry 14).
Ru-1 (4 mol%)
base (equiv.)
solvent, 50 °C, 16 h
1a
2a
3aa
4aa
Entry[a]
Base (equiv.)
Solvent
3aa (%)
4aa (%)
1
K2CO3 (0.5)
NMP
dioxane
toluene
TCE
EtOH
HFIP
AcOH
TFE
TCE
"
18
5
3
The optimized protocol (0.5 mmol benzoic acid 1, 1.5 equiv.
allyl acetate 2, 4 mol% Ru-1, 0.7 equiv. K3PO4, 0.5 mL TCE, 50 °C,
16 h) proved to be applicable to a wide range of aromatic and
heteroaromatic carboxylates in combination with linear or
branched allyl acetates (Table 2). Various functionalities, such as
ether, nitro, sulfonyl, keto, amide, or halo groups were tolerated.
Only free amino or hydroxy groups were found to be incompatible.
The tolerance of bromo groups makes this transformation
orthogonal to traditional cross-couplings, and that of amides
orthogonal to other directed C–H functionalization reactions. On
gram-scale, the reaction gave product 3da in 62% yield without
any further adjustments. Moreover, allyl product 3ba is an
intermediate in Fürstner’s synthesis of salicylihalamides A and B,
natural products presenting cytotoxic properties.[29] Selective
mono-functionalization was observed not only for ortho-, but also
for meta-substituted benzoic acids. For non-substituted benzoic
acid, competing diallylation was observed. α,β-Unsaturated
carboxylic acids reacted only sluggishly. Starting from 1-
cyclohexene-1-carboxylic acid, the allylated product was detected
in 10% 1H NMR yield. The regioselectivity for the allylarenes was
high throughout (>30:1). The complementary protocol (0.5 mmol
benzoic acid 1, 1.5 equiv. allyl acetate 2a, 4 mol% Ru-1, 0.5 equiv.
K3PO4, 0.5 mL TFE, 100 °C, 16 h) afforded 2-propenylarenes,
with stereoselectivities ranging from 2.7:1 to 30:1.
2
-
3
"
trace
60
28
15
-
-
4
5
"
trace
"
trace
6
"
13
7
"
-
8
"
60
20
69
-
5
9
KOAc (0.5)
K3PO4 (0.5)
Li3PO4 (0.5)
K3PO4 (0.7)
"
-
trace
-
10
11
"
11
"
75
81
81
7
trace
trace
8
12[b]
13[b],[c]
14[b], [d]
"
"
"
K3PO4 (0.5)
TFE
72 (30:1)
[a] Reaction conditions: 1a (0.5 mmol), 2a (0.75 mmol), Ru-1 (4 mol%),
base, solvent (1 mL), 50 °C, 16 h, yields determined by 19F NMR
spectroscopy using benzotrifluoride as internal standard, E:Z ratios in
parentheses. [b] solvent (0.5 ml). [c] 60 °C. [d] 100 °C. Ru-1 = [Ru(p-
cymene)Cl2]2. NMP = N-methyl-2-pyrrolidone. TFE = 2,2,2-trifluoroethanol.
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10.1002/anie.201712520
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Besides allyl acetate, α-substituted derivatives were
successfully converted. However, no substituents were tolerated
at the double bond, which is in agreement with reports for Ru-
catalyzed allylations of benzamides or ketoximes.[8c,e] α,α-
Dimethyl allyl acetate gave no conversion, indicating that steric
crowding is an issue in this reaction. Linear products were
exclusively obtained, with E/Z selectivities ranging from 1.2:1 to
>30:1 for the E-product. The E/Z ratios were found not to change
over the course of the reactions. The reason for the unique
selectivity in the case of 3bc is unclear.
be subsequently converted to (-)-mellein, an antifungal natural
product (Scheme 2b).[32]
a)
1) allylation step
2) HOTf
toluene, 50 °C
1) allylation step
2) CuBr/bathophen
NMP, 190 °C
2a
one-pot
one-pot
R = F, 5a 70%
R = OMe, 5b 76%
6a 72% (19F NMR)
b)
BCl3
DCM, 0 °C
5b
mellein 87%
Scheme 2. Optional derivatization reactions.
Table 2. Substrate scope[a]
Ru-1 (4 mol%)
K3PO4 (0.7 equiv.)
All observations made in the course of this study agree with
the proposed catalytic cycle in Scheme 1. When α,α-dideuteroallyl
acetate (D2-2a) was employed, a 12:1 mixture of γ-D2-3aa/α-D2-
3aa was observed confirming the high selectivity for SN2’ type
products that is predicted by the proposed hydroarylation
mechanism (Scheme 3a). If allylruthenium intermediates were
involved, one would have expected to see higher deuterium
incorporation in the α-position, and linear/branched product
mixtures when starting from unsymmetrical substrates. It also
explains the low reactivity of - in comparison to α-substituted allyl
acetates. Control experiments revealed that allyl benzoate 7a can
be converted to the allylated product 3aa, but this intramolecular
version was less efficient than the reaction starting from benzoic
acid 1a, which speaks for an intermolecular pathway (Scheme 3b).
Had 7a been an intermediate, yields of 3aa should have been
comparable to that of Table 1, entry 12. A kinetic isotope effect
(KIE) of kH/kD = 5.7 was observed in competition experiments with
non- and perdeuterated arene substrates. In the corresponding
parallel experiments the KIE was 3.0, which confirms that C–H
cleavage is the rate-determining step (Scheme 3c).
TCE, 50 °C, 16 h
1a-w
2a-c
3aa-va, 3ab-bc
R' = H
R = F, 3aa 79%
R = OMe, 3ba 82%
R = OPh, 3ca 83%
R = Ph, 3da 82% (62%)[b]
R = I, 3ea 74%
R = OCF3, 3fa 80%[c]
R = NO2, 3ga 41%[c]
R = CF3, 3ha 54%[c]
R = CF3, 3ka 70%[c]
R = MeSO2, 3la 60%[c]
R = (CO)Me, 3ia 49%[c]
R = NHAc, 3ja 79%
3ma 70%[c]
3na 85%
3oa 80%[c]
3pa 56%
3qa 71%
3ra 26%[c] (50%[d]
)
3sa 36%[c]
3ta 22%[c]
10:1 C2:C4
3ua 25%[d] monoallyl
3va 42%[d] diallyl
a)
standard
conditions
1a
R' = H
-D2-3aa/-D2-3aa
D2-2a
-D2-3aa
-D2-3aa
4aa 70% (30:1)[e]
R' = Me
4na 60% (2.7:1)[e]
4wa 55% (14:1)[e]
12:1
b)
R' = Ph
standard
conditions
2a
none
2a (1.5 equiv.)
3aa 17%
27%
1a 16%
20%
7a
3ab 70% (1:1.5)
3bb 75% (1:1.9)
3ac 78% (1:1.2)
3bc 64%
2a (0.5 equiv.), AcOH (1 equiv.)
trace
trace
[a] Reaction conditions: 1a-w (0.5 mmol), 2a (0.75 mmol), Ru-1 (4 mol%),
K3PO4 (0.7 equiv.), TCE (0.5 mL), 50 °C, 16 h, isolated yields. [b] 10 mmol
scale. [c] 60 °C. [d] 1H NMR yields. [e] K3PO4 (0.5 equiv.), TFE (0.5 mL),
100 °C, E:Z ratios in parentheses.
c)
standard
conditions
and/or
10 min
1x
D7-1x parallel kH/kD = 3.0 3xa
competitive kH/kD = 5.7
D3-3xa
The C–H allylation can be combined with in situ-derivatization
steps (Scheme 2). Intramolecular hydroacyloxylation occurs
when acidifying the reaction mixture with trifluoromethanesulfonic
acid (HOTf).[30] Protodecarboxylation of the allylated benzoates
occurs when adding a copper catalyst and increasing the
temperature to 190 °C. Product 5b, itself a natural product,[31] can
Scheme 3. Mechanistic investigations and control experiments.
In conclusion, an inexpensive dimeric Ru-complex was found
to efficiently and selectively catalyze the carboxylate-directed
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10.1002/anie.201712520
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COMMUNICATION
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ortho-allylation of benzoic acids under remarkably mild conditions.
The reaction is based on widely available, structurally diverse
(hetero)aromatic carboxylate substrates. Its synthetic utility is
further extend by follow-up isomerization, hydroacyloxylation, or
protodecarboxylation steps.
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Experimental Section
An oven-dried 20 mL vial was charged with [Ru(p-cymene)Cl2]2 (12.2 mg,
0.02 mmol), K3PO4 (76.6 mg, 0.35 mmol) and a benzoic acid (0.50 mmol)
and closed with a septum cap. Under exclusion of air and water, 2,2,2-
trichloroethanol (0.5 mL) and an allyl acetate (0.75 mmol) were added via
syringe. The resulting mixture was stirred at 50 °C for 16 h. After the
reaction was complete, it was diluted with EtOAc (10 mL) and extracted
with aq. K2CO3 solution (3×10 mL). The combined aqueous phases were
acidified with 2M HCl (pH 1-2), then extracted with EtOAc (3×20 mL). The
combined organic layers were washed with brine (20 mL), dried over
MgSO4, filtered, and the volatiles were removed under reduced pressure.
The residue was purified by column chromatography (SiO2, ethyl
acetate/cyclohexane gradient, 1% HCO2H), yielding the corresponding
ortho allylated benzoic acid.
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Acknowledgements
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We thank Umicore for the donation of chemicals, the Alexander
von Humboldt Foundation (fellowship to M.P.D.), and the DFG
(EXC/1069 “RESOLV” and SFB/TRR 88 “3MET”) for financial
support and Dr. Liangbin Huang for helpful discussions.
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Keywords: benzoic acid • C–H activation • allylation • ruthenium
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COMMUNICATION
A. S. Trita, A. Biafora, M. Pichette-
Drapeau, P. Weber, L. J. Gooßen*
[Ru(p-cym)Cl2]2
K3PO4
20 examples
Page No. – Page No.
up to 85% yield
50 °C
Regiospecific ortho-CH Allylation of
Benzoic Acids
A carboxylate-directed ortho-allylation of benzoic acids is achieved in the presence
of [Ru(p-cymene)Cl2]2. The reaction is based on widely available, structurally
diverse (hetero)aromatic carboxylate substrates and proceeds under remarkably
mild conditions. It is widely applicable to (hetero)aromatic benzoic acids and can be
combined with acyloxylation, double-bond isomerization or protodecarboxylation.
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