Cp?Co(III)-Catalyzed Annulation of Carboxylic Acids with Alkynes

Article abstract of DOI:10.1021/acs.orglett.7b00801

A new procedure for oxidative coupling of aromatic and acrylic acids with alkynes has been developed using abundant, nontoxic, and air stable Cp?Co(III) catalyst. The coupling involves initial cyclometalation via weak chelation-assisted C-H bond activation followed by alkyne coordination, insertion, and reductive elimination leading to diverse isocoumarins (α-pyranones) in good yields under mild conditions.

Full text of DOI:10.1021/acs.orglett.7b00801

Letter
pubs.acs.org/OrgLett
Cp*Co(III)-Catalyzed Annulation of Carboxylic Acids with Alkynes
Rajib Mandal and Basker Sundararaju*
Fine Chemical Laboratory, Department of Chemistry, Indian Institute of Technology Kanpur 208016, Uttar Pradesh, India
S
* Supporting Information
ABSTRACT: A new procedure for oxidative coupling of
aromatic and acrylic acids with alkynes has been developed
using abundant, nontoxic, and air stable Cp*Co(III) catalyst.
The coupling involves initial cyclometalation via weak
chelation-assisted C−H bond activation followed by alkyne
coordination, insertion, and reductive elimination leading to diverse isocoumarins (α-pyranones) in good yields under mild
conditions.
Scheme 1. Carboxylic Acid-Directed C−H Bond
Functionalization
irect functionalization of C−H bonds is one of the elegant
Dways to access molecules that are not feasible by traditional
cross coupling methodologies, which requires prefunctionaliza-
tion.1,2 However, overcoming the limitation of strongly chelating
heteroatoms such as N and S is still a major challenge, especially
with first row transition metals.3 Since the pioneering work of
MatsunagaandKanai,theuseofhighvalentCp*Co(III)forC−H
bond functionalization has gained significant attention in the past
few years due to its unique reactivity and selectivity.4,5 The
limitation, however, is the requirement of a heterocycle such as
pyridine and its analogue for cobalt-catalyzed C−H bond
activation (Scheme 1a).6 The use of carboxylic acid as a weakly
coordinating functional group has not been explored until now
with cobalt, although amide and other directing groups have been
exploited.7,8
Isocoumarin and pyrones are widely distributed in many
natural products, which show high biological activity, especially
for antimicrobial,9a,b antifungal,9c anti-inflammatory,9d,e antima-
larial,9f and anti-HIV.9g In 2007, Miura reported the first oxidative
cyclization of aromatic acids with alkynes for the synthesis of
isocoumarins via carboxylate-directed C−H bond functionaliza-
tion (Scheme 1b).10 Since then several groups have reported the
synthesis of isocoumarins using various transition metals such as
Rh(III),11 Ir(III),12 Ru(II),13 and Pd(II)14 under oxidative
conditions (Scheme 1b). To the best of our knowledge, the use
of abundant first row transition metals has not been reported
using carboxylic acid as a directing group. Our own interest has
been focused on the use of base metals for C−H bond
functionalization.15 Herein, we report the first cobalt-catalyzed
oxidative coupling of carboxylic acids with alkynes using
Cp*Co(III) as a catalyst, Cu(II) as an oxidant, and carboxylic
acid as a weakly coordinating group (Scheme 1c), leading to a
variety of isocoumarins.
yield when molecular sieves were introduced (entry 7). As can be
seen from Table 1, ionization of cobalt complex by adding silver
salt does not have any effect on the yield of 3aa (entry 8).
Although several solvents were screened, none of them was found
to give better results than TFE (entry 9).16 Excellent yield of 3aa
in 92% was obtained when the amount of oxidant was increased
from 1.5 to 2 equiv (entry 10).
Reductioninthetemperaturedownto80°Cdidnotimpactthe
product formation (entry 11). However, further lowering in the
temperature led to a drastic reduction in the isolated yield (entry
13).
Subsequently, we further examined the influence of an external
carboxylate source such as sodium acetate; it is known in the
literature that addition of carboxylates promote the reaction.
Introduction of NaOAc in 20 mol % led to near quantitative
formation oftheproductat80°C(entry12). Atthisstage, varying
catalyst loadings and other Co-catalysts were explored. These
were, unfortunately, not to much avail (entries 15−17). The
To begin with, benzoic acid 1a and diphenylacetylene 2a were
employed as the reactants with 10 mol % of Cp*Co(CO)I2 as the
catalyst in 2,2,2-trifluoroethanol (TFE) (0.2 M). The reaction
was carried out at 100 °C for 24 h under an inert atmosphere.
Among the various oxidants that were screened, CuO led to the
best results with the isocoumarin 3aa isolated in 58% yield (Table
1, entries 1−6). A respectable improvement was observed in the
Received: March 21, 2017
© XXXX American Chemical Society
A
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a
Table 1. Results of Optimization of the Reaction
b
entry
[Co] (mol %)
oxidant (equiv)
additive (mg)
temp (°C)
yield (%)
1
Cp*Co(CO)I2 (10)
Cp*Co(CO)I2 (10)
Cp*Co(CO)I2 (10)
Cp*Co(CO)I2 (10)
Cp*Co(CO)I2 (10)
Cp*Co(CO)I2 (10)
Cp*Co(CO)I2 (10)
Cp*Co(CO)I2 (10)
Cp*Co(CO)I2 (10)
Cp*Co(CO)I2 (10)
Cp*Co(CO)I2 (10)
Cp*Co(CO)I2 (10)
Cp*Co(CO)I2 (10)
Cp*Co(CO)I2 (10)
Cp*Co(CO)I2 (5)
[Cp*CoI2]2 (5)
Ag2CO3 (1.5)
AgOAc (1.5)
Ag2O (1.5)
Mn(OAc)2 (1.5)
Cu(OAc)2 (1.5)
CuO (1.5)
CuO (1.5)
CuO (1.5)
CuO (2.0)
CuO (2.0)
CuO (2.0)
CuO (2.0)
CuO (2.0)
CuO (0.5)
CuO (2.0)
CuO (2.0)
CuO (2.0)
CuO (2.0)
100
100
100
100
100
100
100
100
100
100
80
21
20
18
n.d.
7
2
3
4
5
6
58
73
7
MS (80)
MS (80)
MS (80)
MS (80)
MS (80)
MS (80)
MS (80)
MS (80)
MS (80)
MS (80)
MS (80)
MS (80)
c
8
70
d
9
n.d.
10
11
12
13
14
15
16
17
18
92
92
e
80
96
e
60
45
e,f
80
15
40
60
55
80
80
[Cp*CoCl2]2 (5)
80
80
n.d.
a
All reactions were carried out under argon atmosphere, unless otherwise stated, using 1a/2a/[Co]/[oxidant]/4 Å MS in 0.2/0.24/0.02/0.3−0.4
b
c
d
mmol at 100 °C in 2,2,2-trifluoroethanol (1 mL). Isolated yield. 12 mol % of AgSbF6 was added. No reaction was observed with solvents such as
DCE, trifluorotoluene, o-xylene, CH3CN, etc. 20 mol % of NaOAc was used. Oxygen atmosphere. MS = molecular sieves; TFE = 2,2,2-
trifluoroethanol; n.d = not determined.
e
f
withdrawing groups such as Br-, F-, and -CF3 at various positions
of arene led to the corresponding isocoumarins in moderate-to-
good yields (3ga−3ja). The scope of the reaction could be further
extended to thiophene-2-carboxylic acid and naphthalene-1-
carboxylic acid, leading to their respective isocoumarins (3ka−
3la) in very good isolated yields.
Scheme 2. Scope of Acids
To realize the generality of the reaction, methacrylic acid and
acrylic acids were tested under the established reaction
conditions. Indeed, the reactions led to the corresponding
pyrones in moderate-to-excellent yields (3ma−3na). Replace-
ment of carboxylic acids with stronger acid such as sulfonic or
phosphinic acids led to no observable formation of the products
under conditions employed for the carboxylic acids.
The scope of alkynes was further examined as illustrated in
Scheme 3. Symmetrical alkynes such as methyl- and fluoro-
substituted diarylacetylenes gave the products (3ab−3ad) in
excellent yields. Electron-rich alkyne such as 5-decyne, 4-octyne,
and benzyl-protected 1,4-but-2-yn diol provided the correspond-
ing isocoumarins (3ae−3ag) smoothly in excellent yields. We
also investigated the regioselectivity with electronically biased
unsymmetrical internal alkynes. Duetohigh polarizability ofCo−
C bond after cyclometalation, it was anticipated that the
unsymmetrical alkyne would undergo selective insertion to
yield the isocoumarin regioselectively after reductive elimination.
For example, when we employed phenylmethylacetylene 2h with
benzoic acid, the corresponding isocoumarins were obtained with
a regioselectivity of 3.3:1, where the major isomer constitutes the
one in which the phenyl attached the α-carbon to the oxygen
(3ah). A marginal improvement in the regioselectivity was
observed when 4-bromobenzoic acid was used in place of 1a
(3fh). Similar selectivity was observed when the annulation was
extended to alkyl-aryl/heteroaryl substituted acetylenes (3fi−
controlexperiments revealedthattheproduct isnotformedinthe
absence of cobalt catalyst (entry 18).
With the best conditions in hand, the scope of carboxylic acids
(Scheme 2) was examined. Electron donating groups such as Me-
and tBu- at different positions in the aromatic ring (o-, m-, and p-)
gave rise to the corresponding products (3ba−3ea) in excellent
yields. p-Methoxy-substituted benzoic acid yielded 3fa in a very
good yield. The benzoic acids substituted with electron-
B
DOI: 10.1021/acs.orglett.7b00801
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Scheme 3. Scope of Alkynes
Scheme 5. Control Experiments
Scheme 6. Proposed Mechanism
Scheme 4. Overcoming the Limitation of Strong Chelation
3fk). To expand the scope of the reaction, both symmetrical and
unsymmetrical alkynes were tested with methacrylic acid. The
reactions occurred smoothly providing diverse substituted-
pyrones in excellent isolated yields (3me−3mh).
Theinfluenceof acompeting and stronglycoordinating pyridyl
group was examined with an azaindolyl-substituted benzoic acid
1q, Scheme 4. The reaction led selectively to the product derived
by the oxidative coupling of the acid with the alkyne, attesting to
the fact the formation of five-membered metallocyle occurs in
preference to the six-membered one.
To establish the mechanism, control experiments were
performed as shown in Scheme 5. Intermolecular competitive
experiments were conducted between electron-rich and poor
alkynes with benzoic acid. This reaction furnished 3aa and 3ae in
1:1.2 ratio, as established by 1H NMR analysis, indicating that the
insertion is faster with electron-rich alkyne than with electron-
poor alkyne. Competitive experiments were also conducted with
equimolar benzoic acids 1d and 1i with 2a. These reactions
yielded the product derived from the benzoic acid containing
electron-withdrawing group preferably in 1.4:1 ratio. Further, H/
D exchange experiments in the presence of alkyne 2a show
significant amount of deuterium incorporation, suggesting that
cyclometalation is reversible.
intermediateAfollowedbyreversiblecyclometalationmayleadto
cobaltacycle C. More polarized carbon−cobalt in intermediate C
should favor regioselective insertion of alkyne 2 after initial
coordination, leading toseven-membered alkenyl intermediate E.
The latter may undergo reductive elimination to provide the
isocoumarin 3 and Co(I). Cu(II) may reoxidize Co(I) to Co(III),
which is the active species regenerated for next catalytic cycle.
In conclusion, we have demonstrated an efficient, waste-free
andCo-catalyzedoxidativecyclization ofbenzoicandacrylicacids
with internal alkynes for the synthesis of isocoumarins and
pyrones in good-to-excellent isolated yields. Good regioselectiv-
ity was obtained when unsymmetrical alkynes were employed.
We have demonstrated for the first time the use of carboxylic acid
as a weakly chelating functional group for C−H bond
functionalization using Cp*Co catalyst. We have further shown
that the selective carboxylate-directed annulation proceeds
A proposed mechanism for benzoic acid 1 with internal alkynes
2 is shown in Scheme 6. Initial coordination of benzoic acid 1 with
C
DOI: 10.1021/acs.orglett.7b00801
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ASSOCIATED CONTENT
* Supporting Information
TheSupportingInformationisavailablefreeofchargeontheACS
Publications website at DOI: 10.1021/acs.orglett.7b00801.
■
S
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Experimental methods, optimization of reaction con-
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AUTHOR INFORMATION
■
Corresponding Author
*E-mail: basker@iitk.ac.in.
ORCID
Basker Sundararaju: 0000-0003-1112-137X
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support provided by SERB (EMR/2016/000136) to
carryoutthisresearch isgratefullyacknowledged. R.M. isthankful
to IITK and CSIR for his fellowship.
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