Electroreductive Olefin-Ketone Coupling

Article abstract of DOI:10.1021/jacs.0c11214

A user-friendly approach is presented to sidestep the venerable Grignard addition to unactivated ketones to access tertiary alcohols by reversing the polarity of the disconnection. In this work a ketone instead acts as a nucleophile when adding to simple unactivated olefins to accomplish the same overall transformation. The scope of this coupling is broad as enabled using an electrochemical approach, and the reaction is scalable, chemoselective, and requires no precaution to exclude air or water. Multiple applications demonstrate the simplifying nature of the reaction on multistep synthesis, and mechanistic studies point to an intuitive mechanism reminiscent of other chemical reductants such as SmI2 (which cannot accomplish the same reaction).

Full text of DOI:10.1021/jacs.0c11214

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Electroreductive Olefin−Ketone Coupling
Pengfei Hu, Byron K. Peters, Christian A. Malapit, Julien C. Vantourout, Pan Wang, Jinjun Li,
Lucas Mele, Pierre-Georges Echeverria, Shelley D. Minteer,* and Phil S. Baran*
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ABSTRACT: A user-friendly approach is presented to sidestep the venerable Grignard addition to unactivated ketones to access
tertiary alcohols by reversing the polarity of the disconnection. In this work a ketone instead acts as a nucleophile when adding to
simple unactivated olefins to accomplish the same overall transformation. The scope of this coupling is broad as enabled using an
electrochemical approach, and the reaction is scalable, chemoselective, and requires no precaution to exclude air or water. Multiple
applications demonstrate the simplifying nature of the reaction on multistep synthesis, and mechanistic studies point to an intuitive
mechanism reminiscent of other chemical reductants such as SmI2 (which cannot accomplish the same reaction).
ertiary alcohols are an abundant functional group with
olefins is, so far, absent from the literature. The closest
1
Tversatile reactivity that are found in natural products, precedent for the desired transformation was disclosed by
Shono and co-workers (Figure 1D).18 These reports focus
predominantly on intra molecular couplings,18a,b with only a
few inter molecular examples18c,d presented. To the best of our
knowledge, this chemistry has not been applied in the
literature, despite being available for decades, presumably
due to the challenges of using a divided cell setup under an
argon atmosphere and the need for at least a fivefold excess of
the ketone. In this Communication, a new protocol for
electrochemically driven reductive couplings of unactivated
ketones and olefins is presented. This method uses a simple
undivided cell tolerating exogenous air and moisture, exhibits a
broad scope, and can be easily scaled (Figure 1E).
pharmaceuticals,2 and a multitude of useful materials.3
Traditionally, perhaps overwhelmingly, the ketone has served
as a loyal progenitor of this species (Figure 1A) for good
reasons. Every undergraduate organic textbook prescribes a
direct nucleophilic addition of a strong nucleophile, such as
RMgX or RLi, to these electrophilic species.4 Although these
incredibly robust reactions have been employed countless
times, they can indirectly contribute to synthetic inefficiencies,
as their low chemoselectivity often necessitates the use of
protecting groups.5 This dilemma is nicely illustrated (Figure
1B) by examining the patented route to steroid derivative 2.6
Although a Grignard reaction with commercially available
ketone 1 is an obvious disconnection, its use introduces several
protecting group additions, removals, and functional group
manipulations throughout the course of a seven-step sequence
(only one of which forges a C−C bond).
Within the specific realm of intermolecular alkyl nucleophile
additions to unactivated ketones, Grignard and related
organometallic additions are fundamentally limited by their
two-electron mechanisms, which render these nucleophiles
both strongly nucleophilic and often highly basic.4,5,7 Efforts to
tone down their reactivity have been explored, with the most
successful stemming from nucleophiles bearing activated
positions (i.e., allylic, benzylic, propargylic, and α-carbonyl;
see Figure 1C).8,9 Studies employing Zr-,10 Ti-,11 Ru-,12 and
Os-13 based systems, as well as hydrogen atom transfer (HAT)
chemistry,14 have also pointed to the use of olefins as
precursors to species capable of adding to carbonyl groups,
although intermolecular additions into unactivated ketones are
without precedent.15 A less intuitive approach involves an
umpolung disconnection, which renders the ketone the
nucleophilic group through a reductive one-electron approach.
Currently, such approaches have relied primarily on Sm(II),7a,b
Ti(III),16 or photoinduced electron transfer17 to couple
activated olefins and styrenes to ketones. A general
intermolecular reductive coupling of unactivated ketones and
Explorations began by studying Shono’s original condi-
tions18c on a medicinally relevant model substrate pair:
homoallylic alcohol 4 and piperidone 3 (Table 1A). In
principle, the use of Grignard chemistry to perform this
assembly would necessitate the use of a protecting group on 4
and perhaps other precautions due to the enolizability of 3;
hence, more gentle methodologies were sought. Revisiting the
electrochemical method developed by Shono for less ornate
substrates18c only resulted in low yields (Table 1A, entry 1).
This method was pursued with some rigor (see the Supporting
Information for a full listing); however, the yield could not be
improved beyond 17%. Chemical reductants such as SmI2 and
lithium 4,4′-di-tert-butylbiphenylide (LiDBB) were examined
next, and while these methods have been shown to have
success in similar intramolecular scenarios, they were found to
be unsatisfactory for this purpose (entries 2−5, Table 1A).
Developing this chemistry following the guiding principles
Received: October 24, 2020
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A

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Table 1. Optimization of the Reductive Ketone Olefin
Coupling. Comparison to Known Chemical Methods (A)
and a Graphical Optimization Overview of the Newly
Developed Electrochemical Protocol (B)
monosubstituted olefins but performed less successfully with
polysubstituted olefins with compounds 22 and 23 being the
only ones affording good yields. A plausible reason for this lack
of reactivity with more substituted olefins could be due to a
slower rate of addition (for steric reasons) compared to the
lifetime of the ketyl radical.21 In the case of cyclopentene-3-ol,
an interesting finding was that the reaction took place in high
yield with perfect syn diastereoselectivity. The analogous tert-
butyldimethylsilyl (TBS)-protected olefin did not react, nor
did cyclopentene itself. The directing effect of homoallylic
alcohols in this chemistry is notable and perhaps relevant to
the mechanism of the reaction (vide infra).
In a similar fashion, ketones bearing several different
substituents were tolerated (moderate to high yields),
including ethers (26), protected amines (36 and 37), esters
(39), carbamates (43), alcohols (50 and 51), and cyclo-
propanes (52). When 4-substituted cyclohexanones were used,
single diastereomers were isolated with the selectivity
reminiscent of SmI2-promoted reactions (anti, 38 and 39).22
Even cyclic ketones of varying ring sizes (24−39) worked well,
which are often challenging for other methods; reduction
products are often observed when sterically hindered ketones
react with Grignard reagents. For acyclic ketones, the sterics of
the substituents showed a minor impact on the reaction yields
(40−48), although only 25% yield of the desired product was
isolated when very hindered diisopropylketone (45) was used.
Notably, unprotected steroidal substrates 50−52 delivered a
single diastereomeric product in high yield (see the Supporting
Information for structure confirmation).
Figure 1. Tertiary alcohols from simple ketones remain a challenge
for modern synthesis (A). Synthesis of 2 is emblematic of the
problems with Grignard reaction (B). Recent approaches so far do
not address the problem (C). Electrochemical precedent on activated
olefins (D) and a summary of this work (E).
from our own forays19,20 into electrochemistry, specifically
deeply reductive electrochemistry,20 allowed us to hone in on
the sacrificial anode, electrolyte, current density, and
concentration needed to facilitate a high-yielding olefin−
ketone coupling (Table 1B; see the Supporting Information for
a full listing). As graphically illustrated in Table 1B, these three
variables were crucial to the success of this transformation,
which, after optimization, led to a 95% isolated yield of adduct
5 (Table 1A, entry 6). The use of an inexpensive sacrificial
anode (Zn) was ideal, and, in contrast to prior work, a lower
current ensured broad functional group tolerance (10 mA vs
200 mA). Notably, unlike prior precedent, only 2 equiv of the
ketone is required, inexpensive electrodes are employed, and
an operationally simple undivided cell is used. No precautions
are taken to exclude air or moisture, and in fact the reaction
can be run open to the air (cap removed). Finally, the linear
versus branched selectivity is remarkable (>15:1 in most of the
cases).
With these results in hand, the scope of the ketone−olefin
coupling was investigated (Table 2). Several functionalities on
the olefin were tolerated, including free alcohols (1°, 2°, and
3°; 6 to 8), aniline (9), amides (10, 13, 21), nitrile (11), ester
(12), protected amino acid (14), and heterocycles (15−19)
(moderate to high yields). Most of these functional groups
would be challenging to employ using canonical 2e− tactics
such as the Grignard reaction. The reaction tolerated
This reductive coupling could also be applied to simplify
real-world challenges in medicinal chemistry (Scheme 1A).
Thus, the synthesis of the simple vitamin D analogue side
B
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Table 2. Scope of the Electroreductive Olefin−Ketone Coupling
chain 55 was reported through a seven-step route wherein only
one of those steps formed a C−C bond (Scheme 1A-1).23 In
contrast, commercially available oxazolidinone 53 could be
allylated and reduced to yield (S)-2 methyl-4-penten-1-ol 54.
Coupling of 54 with acetone under the developed electro-
chemical conditions then smoothly furnished side chain 55. Of
the three steps required to access 55, two forged key C−C
bonds. Next, the synthesis of DNA-binding metabolite 58
required a five-step sequence with two protecting groups and
the air-sensitive SmI2 to forge a key C−C bond (73%
enantiomeric excess (ee), Scheme 1A-2).24 With the electro-
chemical strategy outlined above, commercially available
aldehyde 56 was converted to the same product in only
three steps via a simple Brown allylation, followed by an
C
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Scheme 1. (A) Electrochemical Ketone−Olefin Coupling Facilitates Rapid Access to Medicinally Relevant Structures such as a
Vitamin D Side Chain (1), a DNA-Binding Metabolite (2), and a Hedgehog Signaling Modulator (3). (B) Batch and Flow
Scaleup
a
Isolated yield
electrochemical addition of acetone/tetra-n-butylammonium
fluoride (TBAF) workup and a final oxidative lactonization
(72% yield, 93% ee). Finally, the steroidal example6 mentioned
in Figure 1 could be addressed in a similar way from the same
starting material (Scheme 1A-3). Thus, the electrochemical
addition of 1 to 2-(Trimethylsilyl)ethoxycarbonyl (Teoc)-
protected amine 59 delivered a single diastereomeric tertiary
alcohol that, after CsF-induced deprotection, delivered 2 in
only two steps. Clearly, the success of the above applications
benefits from the chemoselective (functional group (FG)
tolerant) nature of the electrochemical ketone−olefin coupling.
The reaction can be conducted on 100 g scale (>1 mol) using
a flow system affording a comparable yield to the batch
reaction (Scheme 1B; see the Supporting Information for
details).
The mechanism of this useful reaction (Scheme 2) was next
interrogated through the observation of certain side products
(Scheme 2A), deuterium labeling (Scheme 2B), kinetics, and
voltammetric studies (Scheme 2D,E). A notable limitation of
this chemistry was that ketones bearing α-substituents (such as
60) were not tolerated, and elimination of the α-substituent
was observed (62), suggestive of a ketyl radical intermediate.
Using allyl alcohol (64), the bis addition adduct 65 was
observed, perhaps pointing to a carbanion intermediate
wherein ZnBr2 generated from anodic oxidation could assist
in the departure of the primary alcohol and regeneration of
another olefin. Deuterium labeling using acetone-d6 led to 80%
D
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Scheme 2. Mechanistic Insights from Byproducts (A), Deuterium Labeling (B), Proposed Reaction Mechanism (C), and
a
Voltammetry Studies (D, E)
a
See the Supporting Information for details.
incorporation at the highlighted position (Scheme 2B), further
supporting a carbanion intermediate. When regular acetone
was used in the same experiment but with deuterated
dimethylformamide (DMF), no deuterated product was
observed. Kinetic studies revealed zero-order dependence on
all components except current, indicating that reduction is
purely electrochemical.
acetophenone showed an anodic shift in the cathodic peak
potential denoting a chemical reaction with the ketyl radical
after one-electron reduction. However, even at high
frequencies (100 Hz), the expected second reduction peak
was not observed. We hypothesized that one crucial role of the
sacrificial Zn anode is to provide Zn2+ as a thermodynamic sink
for the second electron reduction. SWV analysis in the
presence of catalytic amounts of ZnBr2 showed three distinct
reduction peaks, where the third peak can be the reduction of
the ZnBr2-coordinated ketone (see the Supporting Informa-
tion). Taken together, these results suggest an ECEC-type
electrochemical mechanism where the ketyl radical formation
(E) takes place at the Sn cathode with strong adsorption
characteristic followed by radical addition (C) into the olefin.
A second one-electron reduction (second E) of the radical
anion to the dianion followed by protonation (second C) and
then workup delivers the final product. The enhanced
reactivity of homoallylic alcohols may be due to improved
binding of the olefin substrate to the cathode surface.
In summary, a chemoselective, scalable method to combine
unactivated olefins and ketones has been developed that
subverts the issues encountered using Grignard reagents in a
conventional retrosynthetic analysis. The scope of this reaction
is broad, and it is operationally simple to perform. A number of
applications demonstrate that the utility extends beyond that
of a simple tactical change, as when strategically employed, it
can dramatically reduce overall step count. Mechanistic studies
point to an intuitive electrochemically driven reductive
pathway that initiates upon the formation of a ketyl radical,
Finally, a series of voltammetric studies was performed
(Scheme 2D,E) to understand how traditionally nucleophilic
ketyl radical can serve as competent coupling partners with
unactivated olefins, as well as to provide evidence for the
overall electrochemical mechanistic sequence as proposed in
Scheme 2C. We hypothesized that the change in its electronic
property and reactivity can be facilitated by a strong adsorption
of the ketyl radical to the Sn electrode. Cyclic voltammetry
(CV) studies were performed using Sn and glassy carbon
(GC) as working electrodes with acetophenone25 as the source
of ketyl radical. Prepeaks on the CV were observed using Sn as
the working electrode but not observed using GC as the
working electrode. These prepeaks are distinct characteristics
of an electron transfer, where the product (ketyl radical) is
strongly adsorbed into the working electrode.26 Furthermore,
the current response observed in the prepeak in Sn was found
to be dependent on the concentration of ketone (see the
Supporting Information).27 This result also rationalizes the
effectiveness of using a Sn cathode over other electrode
materials (see the Supporting Information). Square-wave
voltammetry (SWV) studies were performed, and the results
are summarized in Scheme 2E. The addition of alkene 61 to
E
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Notes
addition to the olefin, and further reduction to a stabilized
carbanion prior to workup. This work is thus another example
of how strongly reducing chemistry can be uniquely facilitated
and enabled in complex settings under electrochemical control
when classical chemical reagents fail.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support for this work was provided by NIH (GM-
118176), NSF (CCI Phase 1 grant 1740656 and Phase II grant
2002158), George E. Hewitt Foundation (P.H.), and Swedish
Research Council (Vetenskapsrådet, VR 2017-00362, B.K.P.).
Authors are grateful to Dr. D.-H. Huang and Dr. L. Pasternack
(Scripps Research) for assistance with nuclear magnetic
resonance (NMR) spectroscopy, to Dr. J. Chen, B. Sanchez,
and E. Sturgell (Scripps Automated Synthesis Facility) for
assistance with HPLC, HRMS, and LCMS, to Dr. J. R. Gage,
Dr. Y. Hsiao, and Dr. E. Zhang (Asymchem Inc.) for assistance
with scale-up reaction.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/jacs.0c11214.
■
sı
All experimental procedures, analysis, and compound
characterization data (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
Phil S. Baran − Department of Chemistry, Scripps Research,
La Jolla 92037, California, United States; NSF Center for
Synthetic Organic Electrochemistry, University of Utah, Salt
Lake City 84112, Utah, United States; orcid.org/0000-
0001-9193-9053; Email: pbaran@scripps.edu
Shelley D. Minteer − Department of Chemistry and NSF
Center for Synthetic Organic Electrochemistry, University of
Utah, Salt Lake City 84112, Utah, United States;
orcid.org/0000-0002-5788-2249; Email: minteer@
chem.utah.edu
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Authors
Pengfei Hu − Department of Chemistry, Scripps Research, La
Jolla 92037, California, United States; NSF Center for
Synthetic Organic Electrochemistry, University of Utah, Salt
Lake City 84112, Utah, United States; orcid.org/0000-
0003-2915-4102
Byron K. Peters − Department of Chemistry, Scripps Research,
La Jolla 92037, California, United States; NSF Center for
Synthetic Organic Electrochemistry, University of Utah, Salt
Lake City 84112, Utah, United States; orcid.org/0000-
0003-2889-1354
Christian A. Malapit − Department of Chemistry and NSF
Center for Synthetic Organic Electrochemistry, University of
Utah, Salt Lake City 84112, Utah, United States
Julien C. Vantourout − Department of Chemistry, Scripps
Research, La Jolla 92037, California, United States; NSF
Center for Synthetic Organic Electrochemistry, University of
Utah, Salt Lake City 84112, Utah, United States;
orcid.org/0000-0002-0602-069X
Pan Wang − Center for Excellence of Process Science,
Asymchem Laboratories (Tianjin) Co., Ltd. TEDA, Tianjin
300457, P. R. China
Jinjun Li − Center for Excellence of Process Science, Asymchem
Laboratories (Tianjin) Co., Ltd. TEDA, Tianjin 300457, P.
R. China
Lucas Mele − Minakem Recherche, Beuvry-la-Forêt 59310,
France
Pierre-Georges Echeverria − Minakem Recherche, Beuvry-la-
Forêt 59310, France
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Complete contact information is available at:
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Author Contributions
The manuscript was written through contributions of all
authors. All authors have given approval to the final version of
the manuscript.
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H
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