Cobalt-Catalyzed Coupling of Benzoic Acid C?H Bonds with Alkynes, Styrenes, and 1,3-Dienes

Article abstract of DOI:10.1002/anie.201711968

A method for cobalt-catalyzed, carboxylate-directed functionalization of arene C?H bonds is reported. Alkynes, styrenes, and 1,3-dienes can be coupled with benzoic acids to provide cyclic products in good yields. The reactions proceed in the presence of a

Full text of DOI:10.1002/anie.201711968

Angewandte
Communications
Chemie
International Edition: DOI: 10.1002/anie.201711968
German Edition: DOI: 10.1002/ange.201711968
ꢀ
C H Activation
ꢀ
Cobalt-Catalyzed Coupling of Benzoic Acid C H Bonds with Alkynes,
Styrenes, and 1,3-Dienes
Tung Thanh Nguyen, Liene Grigorjeva, and Olafs Daugulis*
Abstract: A method for cobalt-catalyzed, carboxylate-directed
ꢀ
functionalization of arene C H bonds is reported. Alkynes,
styrenes, and 1,3-dienes can be coupled with benzoic acids to
provide cyclic products in good yields. The reactions proceed
in the presence of a cobalt(II) hexafluoroacetylacetonate
catalyst, (TMS)2NH base, Ce(SO4)2 cooxidant, and oxygen
oxidant.
ꢀ
T
ransition-metal-catalyzed C H functionalization has been
extensively used in the syntheses of bioactive molecules and
functional materials.[1] Most methods involve the use of
directing groups to ensure regioselective conversion of
ꢀ
Scheme 1. Carboxylic acid C H bond functionalization. 1!2: Pd for
3
2
ꢀ
ꢀ
sp C H; Pd, Ir, Rh, Ru for sp C H bonds, many examples; Fe, Co,
2
3
ꢀ
two examples, limited scope. 1!3!4!2: sp and sp C H; Cu, Fe,
ꢀ
a specific C H bond to give the desired product. In contrast,
Co, Ni, Ru, Rh, Pd; many examples.
ꢀ
non-directed C H functionalization is often limited to
symmetric substrates owing to potential formation of isomer
mixtures. The functionalization can be directed by a number
of common groups, including amines, carboxylates, and
aldehydes.[2] Alternatively, more efficient directing groups
can be installed in one or more synthetic transformations,
since most common functionalities are relatively inefficient in
substantially more available than second- and third-row
transition metals. Only two catalytic methods for carboxyl-
ate-directed sp2 C H bond functionalization mediated by
ꢀ
first-row transition metals have been reported.[5] These
examples present a very significant breakthrough in catalysis.
However, this method requires the use of highly pyrphoric
AlMe3 in combination with a designer ligand for Fe cata-
lysis,[5a] and a limited range of internal alkynes can be
employed in cobalt-catalyzed couplings to afford regioiso-
meric product mixtures.[5b]
ꢀ
promoting C H activation/functionalization. For example, we
and other groups have shown that upon converting carbox-
ylates to aminoquinoline amides, functionalization of sp2 and
sp3 C H bonds can be accomplished under palladium,
ꢀ
rhodium, ruthenium, iron, cobalt, nickel, and copper catalysis
(Scheme 1, 1!3!4!2).[1j,3] Very general reactivity is
observed, thereby enabling arylation, alkylation, fluorination,
sulfenylation, amination, etherification, carbonylation, and
alkenylation of carbon–hydrogen bonds. In contrast, more
Several research groups have reported examples of both
2
ꢀ
low- and high-valent-cobalt catalysis for coupling sp C H
bonds with alkenes and alkynes.[3d–g,6] Specifically, an early
report by Matsunaga and Kanai describes a pentamethylcy-
clopentadienyl (Cp*) cobalt (III) complex as a catalyst for the
ꢀ
weakly coordinating carboxylate groups can direct C H
2
ꢀ
functionalization of sp C H bonds under palladium, iridium,
alkenylation of N-protected indoles to yield pyrrolodindo-
ruthenium, platinum, and rhodium catalysis (1!2).[4] More
lones.[6e] Coupling of alkynes with sp C H bonds in anilides,
2
ꢀ
3
challenging unactivated sp C H bonds in carboxylic acids
esters, and oximes is feasible.[6e–i] Our group has disclosed
ꢀ
can be functionalized under palladium catalysis, with the first
arylation reported by the Yu group in 2007.[4b] It would be
beneficial to employ first-row transition-metal catalysis in
cobalt-catalyzed, aminoquinoline-directed coupling of
2
ꢀ
alkenes, alkynes, and carbon monoxide with sp C H bonds
by employing oxygen as a terminal oxidant.[3d–f] We report
here a general method for cobalt-catalyzed, carboxylate-
ꢀ
carboxylic acid C H bond functionalization for the following
ꢀ
reasons. First, a large variety of starting materials possessing
carboxylate functionality are commercially available or can
be easily prepared, thus shortening the synthetic schemes
since installation and removal (often under harsh conditions)
of the directing group is not required. Second, base metals are
directed functionalization of ortho-C H bonds in benzoic
acids. Alkynes, styrenes, and 1,3-dienes react to afford cyclic
products with excellent regioselectivity.
Reaction optimization was carried out by coupling 1-
hexyne with p-toluic acid (Table 1). The best results were
obtained when (TMS)2NH base, Ce(SO4)2 cooxidant, and
pivalic acid additive were used in trifluoroethanol, affording
78% yield of the cyclic product (entry 1). The pivalic acid
additive is important to increase conversion (entry 2). Other
hindered carboxylic acid additives gave lower yields of
product (entries 3–4). Reaction in hexafluoroisopropanol is
less efficient (entry 5). When a p-toluic acid sodium salt was
used, a lower yield of 6 was obtained (entry 6). Other silyl-
[*] T. T. Nguyen, Dr. L. Grigorjeva, Prof. Dr. O. Daugulis
Department of Chemistry, University of Houston
Houston, TX 77204-5003 (USA)
E-mail: olafs@uh.edu
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under:
https://doi.org/10.1002/anie.201711968.
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Table 1: Optimization of reaction conditions.[a]
Table 2: Reaction scope with respect to alkynes.[a]
Entry Variation from standard conditions
Yield of 2 [%]
1
2
3
4
none
No PivOH
1-AdCOOH instead of PivOH
MesCOOH instead of PivOH
78
61
71
67
5
(CF3)2CHOH instead of CF3CH2OH, no PivOH 45
6[b]
7[c]
8[d]
9
4-MeC6H4COONa instead of 5, no PivOH
24
42
51
0
No Ce(SO4)2
No O2
No Co(hfacac)2
[a] Toluic acid (0.2 mmol), solvent (2 mL), under N2 for 24 h then under
1
O2 for 24 h. Yields are H NMR yields using 1,1,2-trichloroethane
internal standard. [b] (CF3)2CHOH solvent. [c] Toluic acid (0.75 mmol),
CF3CH2OH (7.5 mL), isolated yield. [d] Reaction was kept under N2 for
48 h. PivOH=pivalic acid, 1-AdCOOH=adamantane 1-carboxylic acid,
MesCOOH=2,4,6-trimethylphenylbenzoic acid, hfacac=hexafluoroa-
cetylacetonate.
containing bases are inferior compared to (TMS)2NH.[7]
Notably, the coupling product was obtained in 42% yield
when oxygen was used as the sole oxidant (entry 7). The
reaction is slower under inert atmosphere, thus showing that
both CeIV and oxygen are required for high yields of the
product (entry 8). No conversion was observed when Co-
(hfacac)2 was omitted (entry 9).
The reaction scope with respect to alkynes is presented in
Table 2. Functionalities such as cyano groups, phthalimide,
and olefins are tolerated (7–9). Alkenylation of a THP-
protected propargylic alcohol in combination with in situ
deprotection furnished coupling product 10 in 76% yield.
Silyl and aryl acetylenes are competent substrates (11 and 12).
Internal alkynes are also compatible with the reaction
conditions (13–15). 1-Phenyl-1-propyne selectively produced
a single regioisomer of product in 65% yield (15). Internal
alkynes possessing n-butyl, cyclohexyl, and cyanopropyl
substituents are reactive as well (16–18). The reactions
proceed with selectivity values comparable to those observed
in aminoquinoline benzamide couplings.[3d]
[a] Toluic acid (0.75 mmol), CF3CH2OH (7.5 mL), under N2 for 24 h then
O2 for 24 h. Yields are yields of isolated product. See the Supporting
Information for details. [b] Isolated as a 7:1 mixture of isomers.
[c] Tetrahydropyranyl-protected alcohol was used. Nphth=phthalimide,
TIPS=triisopropylsilyl, Cy=cyclohexyl, Ar1 =3,5-Me2C6H3, Ar2 =4-
CF3C6H4, Ar3 =4-CF3OC6H4.
bonds with olefins is also feasible without any modification of
the standard conditions (Table 4). Reaction of p-toluic acid
with styrene gives product 32 in 67% yield. Coupling of the
same acid with m-bromo- and o-chlorostyrenes affords 33 and
34 in 71 and 48% yields, respectively. Unsubstituted benzoic
acid, methoxy-, and chloro-substituted derivatives couple
with styrene as well, giving products 35–37 in good yields.
Furthermore, terminal 1,3-dienes can be coupled with benzoic
The reaction scope with respect to carboxylic acids is
presented in Table 3. Both electron-rich (19) and electron-
poor (21–23) aromatic acids are successfully coupled with
ꢀ
acids. Use of 1,3-dienes in directed C H functionalization
catalyzed by first-row transition metals is not known.[8]
Alkylation using a 1,2-disubstituted 1,3-butadiene afforded
coupling product 38 in a 63% yield. (+)-Nopadiene reacted
with p-toluic acid to afford the product as a 1:1 mixture of
diastereoisomers in 28% yield (39). Alkyl-substituted olefins
are unreactive.
ꢀ
alkynes. Similar to other transition-metal-catalyzed arene C
H bond functionalizations,[1] the carboxylic acid directed
ꢀ
alkenylation favors reactions at less hindered C H bonds,
resulting in good to excellent regioselectivity (23–25).
Methoxy, chloro, fluoro, vinyl, and propenyl functionalities
are all compatible with the reaction conditions (21–24, 28, and
29). An isocoumarin derived from 1-naphthoic acid was
obtained in 72% yield (27). Heterocycle-containing carbox-
ylic acids are also competent substrates (30, 31).
Based on previous work by us and others, it is likely that
the reaction proceeds via CoIII intermediate 40a, formed
through oxidation of Co(hfacac)2 in the presence of the
benzoic acid ligand (Scheme 2). Insertion of an alkyne into
the cobalt–aryl bond would provide 41. Compound 41 could
undergo direct reductive elimination to 42, or CoIII vinyl could
be protonated to give 44, which could undergo oxidative
We previously reported that the conditions for amino-
quinoline benzamide reactions with alkenes and alkynes are
quite similar.[3d,e] Gratifyingly, coupling of benzoic acid C H
ꢀ
2
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Table 3: Reaction scope with respect to benzoic acids.
Table 4: Alkylation of benzoic acids.
[a] Acid (0.75 mmol), olefin (1.5 equiv), CF3CH2OH (7.5 mL), N2 for 24 h
then O2 for 24 h. Yields are those of isolated products. See the
Supporting Information for details. [b] Isolated as a 10:1 regioisomer
mixture. [c] Isolated as 1:1 diastereoisomer mixture.
44 and 45 were reacted under standard conditions. For
reaction with 44, product 42 was not formed, while 45 gave 20
in good yield. Distinguishing between cobalt acetylide and
migratory insertion mechanisms should be possible by
employing deuterated acetylene such as 46-d1, provided that
there is no H/D scrambling under the reaction conditions.
Unfortunately, extensive scrambling was observed, as shown
in Scheme 2. Thus, it is likely that the reaction proceeds via
a cobalt acetylide intermediate, but a migratory insertion
mechanism (40!41) cannot be excluded.
[a] Acid (0.75 mmol), CF3CH2OH (7.5 mL), under N2 for 24 h then O2 for
24 h. Yields are yields of isolated product. See the Supporting
Information for details. [b] N2 for 24 h then O2 for 48 h. [c] Isolated as
a 7:1 mixture of isomers. [d] Isolated as a 97:3 mixture of isomers.
[e] Isolated as a 98:2 mixture of isomers. [f] Isolated as a 10:1 mixture of
isomers.
cyclization to give 42. Additionally, an alternative mechanism
with a cobalt acetylide intermediate as proposed by Ribas in
a different system[9] [40a (X = OCOR or other anion)!40b
(X = alkynyl)!43!42] is feasible, despite the fact that
internal alkynes are reactive. We note that the timing of
Co–aryl versus Co–alkynyl bond formation is not clear at this
point for our system. To distinguish between those pathways,
In conclusion, we have developed a method for cobalt-
catalyzed coupling of alkynes, styrenes, and 1,3-dienes with
2
ꢀ
sp C H bonds in benzoic acids. The reaction proceeds in
trifluoroethanol solvent with a Co(hfacac)2 catalyst, oxygen
oxidant, Ce(SO4)2 cooxidant, and (TMS)2NH base. Both
terminal and internal alkynes are reactive, and excellent
Scheme 2. Mechanistic considerations.
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available cobalt salt and simple carboxylate directing group to
2
ꢀ
achieve sp C H functionalization are major advantages of
this method. Future work will involve expansion of reaction
scope with respect to alkenes.
Acknowledgements
We thank the Welch Foundation (Chair E-0044) and NIGMS
(Grant No. R01GM077635) for supporting this research.
Conflict of interest
The authors declare no conflict of interest.
ꢀ
Keywords: alkenylation · benzoic acid · C H activation · cobalt ·
olefin
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ꢀ
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Manuscript received: November 21, 2017
Version of record online: && &&, &&&&
4
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Communications
ꢀ
C H Activation
T. T. Nguyen, L. Grigorjeva,
O. Daugulis*
&&& — &&&
Cobalt-Catalyzed Coupling of Benzoic
A step in the right direction: A cobalt-
cyclic products in good yields. The reac-
ꢀ
Acid C H Bonds with Alkynes, Styrenes,
and 1,3-Dienes
catalyzed, carboxylate-directed function-
tions proceed in the presence of a cobalt-
(II) hexafluoroacetylacetonate catalyst,
(TMS)2NH base, O2 oxidant, and Ce-
(SO4)2 cooxidant.
ꢀ
alization of arene C H bonds is reported.
Alkynes, styrenes, and 1,3-dienes are
coupled with benzoic acids to provide
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