Proton-Coupled Electron Transfer: Transition-Metal-Free Selective Reduction of Chalcones and Alkynes Using Xanthate/Formic Acid

Article abstract of DOI:10.1021/acs.orglett.9b00635

Highly chemoselective reduction of α,β-unsaturated ketones to saturated ketones and stereoselective reduction of alkynes to (E)-alkenes has been developed under a transition-metal-free condition using a xanthate/formic acid mixture through proton-coupled electron transfer (PCET). Mechanistic experiments and DFT calculations support the possibility of a concerted proton electron-transfer (CPET) pathway. This Birch-type reduction demonstrates that a small nucleophilic organic molecule can be used as a single electron-transfer (SET) reducing agent with a proper proton source.

Full text of DOI:10.1021/acs.orglett.9b00635

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Proton-Coupled Electron Transfer: Transition-Metal-Free Selective
Reduction of Chalcones and Alkynes Using Xanthate/Formic Acid
Ramanathan Prasanna, Somraj Guha, and Govindasamy Sekar*
Department of Chemistry, Indian Institute of Technology Madras, Chennai 600036, Tamil Nadu, India
S
* Supporting Information
ABSTRACT: Highly chemoselective reduction of α,β-unsatu-
rated ketones to saturated ketones and stereoselective reduction
of alkynes to (E)-alkenes has been developed under a transition-
metal-free condition using a xanthate/formic acid mixture
through proton-coupled electron transfer (PCET). Mechanistic
experiments and DFT calculations support the possibility of a
concerted proton electron-transfer (CPET) pathway. This Birch-
type reduction demonstrates that a small nucleophilic organic
molecule can be used as a single electron-transfer (SET) reducing
agent with a proper proton source.
Scheme 1. Selective Reduction of C=C Bond of α,β-
Unsaturated Carbonyl Compound
hemoselective reduction plays a significant role in
1
Csynthetic chemistry. The selective reduction of a C=C
bond in an α,β-unsaturated carbonyl compound is among one
of the highly potent and challenging functional group
transformations in organic chemistry. Although there are
several ways to reduce the C=C bond of an α,β-unsaturated
ketone selectively, all of them have their own merits and
demerits. Transition-metal-catalyzed transfer hydrogenation2
has proven to be an effective method for such transformations
and has emerged as an alternative method for the traditional
hydrogenation with hydrogen gas (H2, Pd/C) (Scheme 1A
(i)). However, the use of a relatively expensive metal complex,
long reaction time, and metal contaminations are the general
limitations of this elegant method.3
Dissolving metal reductions are also known for the selective
reduction of the C=C bond of α,β-unsaturated ketones. The
frequently used reagents are low-valent metals, which can easily
donate one or two electrons to the molecules with an
accessible LUMO in protic solvents. For examples, Li in liquid
NH3 (Birch-type reduction),4 Mg in MeOH,5 SmI2 in H2O,6
and Zn in protic medium7 have been used for the selective
reduction of α,β-unsaturated ketones (Scheme 1A (ii)). But,
metal leaching, a long reaction time, and cost of the metal
constitute a persistent problem.
Therefore, the investigation of a simple, efficient, and
transition-metal-free new reductive system for the chemo-
selective reduction of an α,β-unsaturated ketone is highly
desirable
Recently, a number of neutral organic molecules known as
“super electron donors” (SEDs) have been developed.8 These
SEDs undergo spontaneous loss of one or two electrons and
can operate under milder reaction conditions than the reaction
conditions required for dissolving metal reductions. Interest-
ingly, the reduction potentials of these SEDs can be tuned by
the appropriate modification of their structure.
Proton-coupled electron transfer (PCET) is another efficient
process where the rate and energetics of the electron transfer
(ET) can be modulated with appropriate proton sources.9
According to Mayer et al. the term PCET encompasses the
redox process where the proton transfer (PT) and ET among
one or more reagents by a concerted or stepwise mechanism.9a
Received: February 20, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b00635
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
During PCET, the protons can modulate the electron-transfer
process even if the protons do not transfer.9a,10 Clearly, the
addition of proper proton sources may offer a new general
approach to enable an otherwise elusive ET process or to
accelerate a slow ET process.
Scheme 3. Substrate Scope with Various Enones
Recently, the reductive PCET has been employed for the
reduction of the functional groups such as alkenes and
ketones.11 However, their application in selective reduction of
functional groups in organic synthesis is not known.
Considering the redox properties of potassium ethyl xanthate
and their utility in the redox process,12 herein, we describe how
the easily available xanthate salt can act as a single electron
donor and can reduce the C=C bond selectively in α,β-
unsaturated carbonyl compounds in the presence of appro-
priate proton sources by following a PCET pathway (Scheme
1B). Importantly, this methodology shows that an easily
available nucleophile can be used as an SET reducing agent in
the presence of a proper proton source.
We started our investigation by examining the reaction
between the chalcone 1a (1 equiv) and potassium ethyl
xanthate (2 equiv) in DMF at 100 °C (Scheme 2). After 48 h,
a
Reaction conditions: 1 (0.5 mmol), xanthate (2 equiv), HCO2H (2
equiv), DMF (2 mL) at 130 °C. Reaction conditions: 1,3-
diphenylprop-2-yn-1-one (0.5 mmol), xanthate (2 equiv), HCO2H
b
Scheme 2. Chemoselective Reduction of Chalcone by
KCS2OEt/HCO2H
(2 equiv), DMF (2 mL) at 130 °C.
carbonyl) also reacted smoothly and furnished the desired
products in high yields (2l, 2m).
Substrates with the electron-rich and electron-deficient
benzoyl rings provided a good yield of the products (2n−
2o). Aliphatic ketone 2p is well-tolerated under the reaction
conditions, although low yield of the product was observed.
Substrates with aromatic rings such as thiophenyl and
naphthyls were also suitable under the optimized conditions,
resulting in moderate to good yields (2q−2t). The yield of the
product was slightly reduced when the methyl group was
present at the α-position of the ketone (2u).
the reduced product 1,3-diphenylpropan-1-one 2a was formed
in 60% yield along with the Michael addition product 3a in
13% yield (Scheme 2a).13 This result indicated that the
xanthate can act as an electron donor instead of a nucleophile.
As DMF is a hygroscopic solvent and normal DMF contains
some amount of water, we anticipated that the extent of
electron-transfer process may be dependent on the concen-
tration of the proton present in the reaction mixture. We
observed that the formation of 2a varied with different external
proton sources and was completely suppressed when the
reaction was carried out in dry solvent under nitrogen
atmosphere (Table S1). Finally, a quick optimization of the
reaction conditions showed that a 99% yield of 2a can be
obtained selectively with 2 equiv of xanthate and 2 equiv of
formic acid in 2 mL of DMF at 130 °C in 1.5 h (Scheme 2b).
With this trustworthy protocol in hand, we then switched
our attention in examining the scope of substrates, and the
results are summarized in Scheme 3. The presence of electron-
rich substituents such as methyl and methoxy at the para-
position of the phenyl ring (β- to carbonyl) offered the desired
products in good yields (2b−2d). Substrates with electron-
withdrawing groups attached at the para-position of the phenyl
rings were also compatible under the reaction conditions (2e−
2h). When the phenyl ring (β- to carbonyl) contains the
electron-releasing group at the ortho- and meta-positions, the
yield of the products was moderate to good (2i−2k).
Substrates with sterically crowded phenyl rings (β- to
The high selectivity of the present protocol was established
when the electron-deficient alkene group was reduced
selectively in the presence of another alkene group (2v). The
free amine group was also observed to be well-tolerated under
the optimized conditions, although a low yield of the reduced
product was obtained for such substrates (2w, 2x). Finally, the
reduction was examined for (E)-1,4-arylbut-2-ene-1,4-dione. In
all the cases, the corresponding saturated 1,4-ketones were
obtained in high yields (Schemes 4 and 5a−d).
Our attention then turned to examine the efficiency of our
PCET protocol for the hydrogenation of alkynes. Controlled
hydrogenation of alkynes was achieved with excellent stereo-
Scheme 4. Substrate Scope with Various Diketones
B
DOI: 10.1021/acs.orglett.9b00635
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Organic Letters
Letter
Scheme 5. Substrate Scope with Various Diaryl Alkynes
Scheme 7. Mechanistic Investigation for PCET Pathway
a
Reaction conditions: 6 (0.5 mmol), xanthate (2 equiv), HCO2H (2
b
equiv), DMF (2 mL) at 130 °C. Reaction conditions: 6 (0.5 mmol),
xanthate (2 equiv), H2O (10 equiv), DMF (2 mL) at 140 °C.
selectivity to provide E-alkenes in good to excellent yield
(Scheme 5).14
As shown in Scheme 5, the reaction was efficient with a
broad spectrum of diphenyl alkynes bearing electron-rich,
electron-poor, neutral, and heterocyclic aromatic rings (7a−7i)
Finally, to check the competence of this reduction in large
scale, a gram scale (1.04 g) reaction was conducted under the
optimized conditions, and the expected 1,3-diphenylpropan-1-
one was obtained in 96.5% yield (Scheme 6).
mixture (Scheme 7a). The ratio of the products 1a and 1n was
observed to be 1.5:1 at the end of the reaction.18 This result is
also inconsistent with the initial rate-limiting electron-transfer
pathway, because the methoxy-group-containing chalcone 1n
would form a more unstable anion radical intermediate after
electron transfer, and consequently, a greater difference in the
rate of generation of the product 2a and 2n would be observed.
As the reaction is viable in the presence of 2 equiv of acetic
acid (Table S2, entry 16), product isotope effect (PIE)
experiments were carried out (Scheme 7b) with the substrate
1a in the presence of different mixtures of acetic acid and
acetic acid-d4.18 No deuterium-labeled product was observed
with 3:1 and 1:1 mixtures of acetic acid and acetic acid-d4.
However, with 1:3 mixture of acetic acid and acetic acid-d4, a
high product isotope effect (kH/kD = 6.36) was observed at the
α-carbon to the keto group.18 This observation is consistent
with the concerted proton electron transfer or CPET
pathway.17
The possibility of proton exchange between the starting
material and acetic acid-d4 as well as between the product and
acetic acid-d4 during the course of the reaction was examined,
and no α-H exchange with deuterium was observed.18
Finally, the thermochemistry of this PCET pathway was
studied18 using quantum chemical calculations.9a,19 Again, the
CPET pathway was observed to be favorable.
To understand more about the reaction, the reduction of 1a
was carried out in the presence of different amounts of
TEMPO (Scheme 8a). This observation suggested that the
reaction might follow a radical pathway.
Scheme 6. Gram Scale Reaction
Three possible pathways can be proposed for this xanthate
mediated selective reduction of chalcones in the presence of
formic acid: (i) consecutive PT and ET; (ii) consecutive ET
and PT; (iii) concerted transfer of electron and proton in a
single kinetic step, which is known as concerted proton
electron transfer or CPET.15 All three of these pathways are
considered as subsets of the PCET pathway.9a,16
The possibility of the pathway (i) (i.e., the initial PT
followed by the ET) was probed with a competition
experiment between 1a and 1b (Scheme 7a) following Mayer’s
work.17 The reduction of a 1:1 ratio of 1a and 1b with a
limited xanthate and formic acid mixture, yielded 2a and 2b in
the ratio of 1.4:1.18 This result is inconsistent with the initial
rate-limiting proton transfer, because the methoxy-group-
containing chalcone 1b would form a more stable benzylic
carbocation intermediate after the proton transfer, and
consequently, the generation of the product 2b would be
faster than that of 2a.
A plausible mechanism for this reaction was proposed
(Scheme 8b). After PCET, the reaction proceeds through the
radical intermediate 9 and generates the byproduct dixanth-
ogen 10, which was detected in GC−MS. The intermediate 9
can be tautomerized to generate radical intermediate 11. The
radical 11 can be transformed to product 12 via an additional
proton and electron transfer from the HCOOH/xanthate
mixture. This proton and electron transfer can be concerted or
stepwise. However, a detailed investigation of the mechanism
of this reaction is presently underway.
The possibility of the pathway (ii) (i.e., the initial ET
followed by the PT) was checked by recording the redox
potential of 1a and potassium ethyl xanthate using a cyclic
voltameter.18 The results indicated that electron transfer from
potassium ethyl xanthate (E1/2 (oxidation) = −0.03 V vs Ag/
Ag+ in DMF) to 1a (E1/2 (oxidation) = 0.29 V vs Ag/Ag+ in
DMF) is unfavorable.
In conclusion, we have developed a PCET protocol for
selective reduction of a C=C functionality of α,β-unsaturated
carbonyl compounds with a mixture of xanthate and formic
A competition experiment between 1a and 1n (1:1 mixture)
was also carried out with a limited xanthate and formic acid
C
DOI: 10.1021/acs.orglett.9b00635
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b00635.
■
S
Detailed experimental procedures, characterization data,
and copies of NMR spectra (PDF)
(13) LaLonde, R. T.; Codacovi, L.; He, C. H.; Xu, C. F.; Clardy, J.;
Krishnan, B. S. J. Org. Chem. 1986, 51, 4899−4905.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: gsekar@iitm.ac.in.
ORCID
(14) E-Selectivity is confirmed by melting point of commercially
available E-stilbin and also by crude NMR of (E)-1-methyl-4-
styrylbenzene.
́
(15) Costentin, C.; Evans, D. H.; Robert, M.; Saveant, J. M.; Singh,
P. S. J. Am. Chem. Soc. 2005, 127, 12490.
Govindasamy Sekar: 0000-0003-2294-0485
Notes
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49, 337. (b) Weinberg, D. R.; Gagliardi, C. J.; Hull, J. F.; Murphy, C.
F.; Kent, C. A.; Westlake, B. C.; Paul, A.; Ess, D. H.; McCafferty, D.
G.; Meyer, T. J. Chem. Rev. 2012, 112, 4016.
(17) Kolmar, S. S.; Mayer, J. M. J. J. Am. Chem. Soc. 2017, 139,
10687−10692.
(18) See Supporting Information for details.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
G.S and S.G thank IIT Madras for the IRDA project. We thank
DST-FIST (for instrumentation facilities and HPCE) and IIT
Madras (for computational facilities). R.P. thanks DST-SERB
for NPDF.
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Chem. 2016, 40, 7431−7436. (d) Meyer, T. J.; Huynh, M. H. V.;
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DOI: 10.1021/acs.orglett.9b00635
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