In Situ Generated AgII-Catalyzed Selective Oxo-Esterification of Alkyne with Alcohol to α-Ketoester: Photophysical Study

Article abstract of DOI:10.1021/acs.orglett.5b03484

An expert and easy one-step catalytic method for the multi O-C coupling of alkyne is developed for the synthesis of valuable α-ketoesters and their chiral analogues, in contrast to the generation of esters by a noncatalytic method. The in situ generated powerful Ag^II catalyst from AgOTf is the workhorse in the oxidative grafting of alkyne with PhIO and alcohol. The radical mechanism is confirmed in our controlled experiments and UV-vis study.

Full text of DOI:10.1021/acs.orglett.5b03484

Letter
pubs.acs.org/OrgLett
In Situ Generated AgII-Catalyzed Selective Oxo-Esterification of
Alkyne with Alcohol to α‑Ketoester: Photophysical Study
Radha M. Laha, Saikat Khamarui, Saikat K. Manna, and Dilip K. Maiti*
Department of Chemistry, University of Calcutta, University College of Science, 92 A. P. C. Road, Kolkata 700009, India
S
* Supporting Information
ABSTRACT: An expert and easy one-step catalytic method for the multi
O−C coupling of alkyne is developed for the synthesis of valuable α-
ketoesters and their chiral analogues, in contrast to the generation of
esters by a noncatalytic method. The in situ generated powerful AgII
catalyst from AgOTf is the workhorse in the oxidative grafting of alkyne
with PhIO and alcohol. The radical mechanism is confirmed in our
controlled experiments and UV−vis study.
irect introduction of two vicinal functional groups into a
cysteine and serine proteinase inhibitors α-ketoester-β-amines,
thrombin inhibitor α-ketoester peptides, cancer cell growth
inhibitors and insecticidal antibiotic respirantin, and anti-
influenza-active angelicin.8 α-Ketoesters bearing strongly elec-
tron-deficient carbonyl and neighboring binding-capable ester
functionalities make them useful synthons for asymmetric
reduction, fluorination, aminohydroxylation, and aldol reactions,
tandem heterocyclization, lactonization, construction of bio-
active natural products, and efficient epoxidation catalysis and
have strongly chelation-guided optical properties.9 α-Ketoesters
were synthesized using PdII, CuI, Cu powder, and I2-mediated
coupling of alcohol to carbon monoxide, 1,3-diketones, 1,3-
ketoaldehydes, and acetophenones, respectively.10 α-Function-
alized esters were the preferred precursor for α-ketoesters, which
D
C−C triple bond has found immense application in recent
times.1,2 The intermolecular heterodifunctionalization is an
especially attractive process to achieve valuable synthons,
intermediates, pharmaceuticals, bioactive natural products, and
their synthetic analogues.1 In a continual effort to study the
reaction of alkynes with λ3-hypervalent iodines3 under mild
reaction conditions,1b,4 we envisaged that a terminal alkyne can
be directly transformed into valuable α-ketoesters (4, route b,
Scheme 1) through simultaneous installation of two oxo groups
Scheme 1. Selective Synthesis of α-Ketoester over Ester
n
were achieved using RhI, BuLi, Bu4NF−KF, RuII, and PDIA−
H2SO4.11 There are also a few other reported methods.12
Syntheses of α-ketoesters were also reported through oxidation
of trimethylsilyl-activated acetylenes using OsO4−tBuO2H,13a
Co(salen)-catalyzed reaction,13b and a similar two-step reaction
using the strong oxidant KMnO4 under basic conditions.13c
Direct synthesis of α-ketoesters and their chiral analogues
through coupling of alkyne with alcohol under low catalyst
loading will be an exciting addition to the existing approaches.
We have reported several benign strategies using PhIO under
neutral conditions.7a−d To synthesize α-ketoester 4a, this work
begins with (Table 1) treatment of a mixture of 4-
biphenylacetylene (1a, 1 mmol), PhIO (3 mmol), and methanol
(1 mmol) in 1,2-ethylene dichloride (EDC) with a suitable
catalyst (1 mol %). Our early catalyst screening using several
potential metal salts and complexes (only two are only shown,
entries 1 and 2, Table 1) were unsuccessful. Gratifyingly, upon
use of metal catalysts such as FeIII, Pd0, IrIII, and RhIII the
reactions were successful (entries 3−6) in producing the desired
product 4a. However, the poor yields were a major concern of
these reactions, and the yields were not improved (18−25%)
into both the alkyne carbons and O−C coupling to ≡C−H with
alcohols. Interestingly, during preparation of our oxidative
difunctionalization strategy, Guo and co-workers published a
noncatalytic reaction to esters (3, route a, Scheme 1) through
cleavage of alkynes with fluorinated λ3-hypervalent iodine
[PhI(OCOCF3)2] at 60 °C (15 h).5 Thus, it is a great challenge
for direct syntheses of α-ketoesters (4, route b) without
generation of ester 3. We were looking for efficient catalyst,
neutral hypervalent iodine, and mild reaction conditions to avoid
breakage of the labile keto-ester bond (C2−C1) of 4, which may
produce the byproduct 3 (route b). AgII species6 was the catalyst
of choice, and PhIO7 was chosen as an oxygen source for keeping
reaction medium neutral, rather than making harmful acidic
conditions for the use of PhI(OCOR)2.
α-Ketoesters and their analogues are widespread in Nature,
valuable pharmaceuticals, and bioactive natural products such as
Received: December 8, 2015
© XXXX American Chemical Society
A
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Table 1. Survey and Optimization of the Reaction
Table 2. Synthesised α-Ketoesters
b
c
d
entry
catalyst
solvent
temp (°C) time (h) yield (%)
1
Ni(OAc)2.4H2O
RuCl3.xH2O
FeCl3
EDC
EDC
EDC
EDC
EDC
EDC
EDC
EDC
EDC
EDC
EDC
EDC
EDC
EDC
80
80
80
80
80
80
rt
8
10
8
2
3
20
25
18
22
58
68
71
70
63
4
Pd(PPh3)4
IrCl3
8
5
6
6
RhCl3.3H2O
AgOTf
4
7
12
8
AgOTf
80
40
40
40
40
40
80
40
40
40
40
40
40
40
1.5
9
AgOTf
1.5
1.5
1.5
8.0
9.0
1
e
10
AgOTf
f
11
AgOTf
AgOTf
g
12
13
14
15
16
17
18
19
20
21
12
50
65
62
45
60
40
25
20
AgOTf
AgOTf
AgOTf
AgOTf
AgClO4
AgNO3
AgVO3
Ag2O
MeOH
THF
1.5
1.5
1.5
2
PhCH3
EDC
EDC
3
EDC
6
EDC
6
a
b
c
PhIO (3 mmol), 1a (1 mmol), and 2a (1 mmol). 1 mol %. 5 mL.
d
e
f
Purified by column chromatography. 0.1 mol %. PhIO (2.5 mmol).
g
No PhIO.
with higher catalyst loading and reaction temperature.
Surprisingly, the yield of 4a was significantly improved (58%,
entry 7) upon use of AgOTf (1 mol %) at ambient temperature.
Both the yield (71%) and reaction rate (1.5 h) were further
improved under warming (40 °C) conditions (entries 8−11).
Optimized conditions were developed using only 0.1 mol % of
AgOTf catalyst to complete the reaction within 1.5 h (entry 10)
in 70% yield. Our controlled experiments (entries 11−14)
confirm the presence of AgOTf catalyst (0.1 mol %) and oxidant
PhIO (3 mmol) were essential for the heterodifunctionalization
process. EDC was found as the best solvent (entries 10 and 15−
17). Other silver salts (entries 18−21) were not found to be
better catalysts.
The tolerance of various functionalities was successfully
examined for this new method (Scheme 2) through synthesis
of a wide range of compounds bearing both unsubstituted and
substituted aromatic rings (Table 2), heterocycles (4t), biphenyl
systems (4a−e,g,h), and naphthalene ring (4i). The manipu-
lation of substrates has been achieved using primary, secondary
(4d), and long-chain alcohols (4e). Arylalkynes bearing
deactivating group halogen, nitrile, nitro, ketone, and ester
Scheme 2. Synthetic Route to α-Ketoesters
(4m−q, entries 13−17) were tolerated, but alkene was not
tolerated. The unorthodox carbonylation via an esterification
strategy to functionalized α-ketoesters (4a−u) was rapid (1.0−
4.0 h) and moderate to high yielding (52−80%). The substrate
(1) bearing a strongly electron-rich aromatic substituent such as
alkyne 1c and 1k (entries 9, 19, and 21) reduced the yield of 4i,
4s, and 4u substantially (52−55%) because of the formation of
B
DOI: 10.1021/acs.orglett.5b03484
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the corresponding degradation byproduct esters (3, Scheme 1).
The structure of compound 4g was confirmed by single-crystal
X-ray diffraction data analyses (Scheme 2).14
Based on our control experiments, UV−vis study, and
literature evidence,6,14,15 we have proposed a radical mechanism
for this reaction (Scheme 3). PhIO is a well-known λ3-
To explore the scope of the benign strategy for synthesis of
thermally labile chiral α-ketoesters we have carried out the
reaction using secondary chiral alcohols (5, Table 3). Gratify-
Scheme 3. Possible Reaction Pathways
Table 3. Scope of the Strategy for Chiral α-Ketoesters
ingly, chiral alcohols bearing sterically congested menthyl (5a,
entry 1, Table 3), adamentyl (5b, entry 2), and norbornyl (5c,d,
entries 3 and 4) groups smoothly underwent an oxidative
difunctionalization reaction to afford optically pure new α-
ketoesters (6a−d, Table 3). Most of the reported methods have
limits for direct access to the chiral α-ketoesters.
hypervalent iodine reagent that follows a radical reaction
pathway.17 PhIO transforms procatalyst AgI into transient AgII
species through single electron capturing, which converts 1 into
the Ar−C≡C• radical followed by O−C coupling with alcohol
(2) to deliver an intermediate I (eq i). The intermediate I for 4a
was identified by mass spectrometry (Supporting Information),
which appeared at retention time 20.20 min with desired mass
208 (C12H9−CC−OCH3). The reaction is expected to pass
through formation of II and transfer of “O” from PhIO leading to
construction of 4. Transfer of both “O” from PhIO was
established using PhI18O, which produced 18O2−4a (eq iii) of
mass 245.0948 (M + H). On the other hand, installation of two
“oxo” groups and migration of Ar with release of CO2 may
produce a simple ester (eq ii), which was observed by Guo et al.
(3, Scheme 1).5 Upon use of strongly activated alkynes such as 1c
and 1k (entries 9, 19, and 21, Table 2), we found corresponding
esters (3) about 5% under the reaction conditions, which were
increased by elevated temperature and longer reaction time.
Herein, transformation of intermediate II to product 4 is
expected to be a fast process because our attempts for trapping
the intermediate II were unsuccessful (eq iv,v). Surprisingly,
upon use of electronic and sterically congested triphenyl carbinol
(2h) and diphenylphosphinic acid (7) the corresponding
intermediates IIv and 8 were trapped, isolated, and characterized.
This supports the proposed mechanism.
The AgII complex is a metastable species15 and appeared as a
transient intermediate. In our control experiment, we noted that
the reaction was almost arrested in the presence of radical
scavenger TEMPO. This result suggested the reaction follows a
radical pathway. Our UV−vis study of the dynamic reaction
along with separate solutions containing EDC and AgOTf,
AgOTf with PhIO, and a combination of AgOTf, PhIO, and
substrate 4-phenylphenylacetylene (Figure 1) reveals the
Figure 1. UV−vis study and detection of AgII species.
In conclusion, we have demonstrated an in situ generation of
robust AgII catalyst from a procatalyst AgI using PhIO under
neutral reaction conditions. Our preliminary mechanistic study
reveals that carbonylation via esterification of alkynes follows the
radical pathway. It is an expert, selective, and simple method for
direct synthesis of α-ketoesters through oxidative grafting of
terminal alkynes and alcohols using very low catalyst loading.
The simple and benign one-step strategy for the multi O−C
coupling reaction brings another frontier into metal catalysis,
which is compatible for easy access to valuable chiral α-
ketoesters.
appearance of a new peak at 371 nm. The peak was intensified
upon addition of K2S2O8. Kochi and Anderson15 achieved similar
results using a solution of AgNO3 and stronger electron acceptor
S2O82−, which absorbed at 381 nm15a because of forming AgII.
With these experiments we have not only confirmed that this
reaction is catalyzed by in situ produced metastable AgII species
from procatalyst16 AgOTf but also discovered formation of the
active oxidative radical AgII catalyst upon treatment of λ3-
hypervalent iodines. It will definitely find considerable
application in frequently used AgI-hypervalent iodine mediated
reactions.
C
DOI: 10.1021/acs.orglett.5b03484
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Letter
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
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Detailed experimental procedures, XRD, and spectro-
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AUTHOR INFORMATION
Corresponding Author
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*E-mail: dkmchem@caluniv.ac.in.
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Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
Financial support of DST (SR/S1/OC-05/2012 and SR/S5/
GC-04/2012) and UGC are gratefully acknowledged.
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