New Bisoxazoline Ligands Enable Enantioselective Electrocatalytic Cyanofunctionalization of Vinylarenes

Article abstract of DOI:10.1021/jacs.9b03296

In contrast to the rapid growth of synthetic electrochemistry in recent years, enantioselective catalytic methods powered by electricity remain rare. In this work, we report the development of a highly enantioselective method for the electrochemical cyanophosphinoylation of vinylarenes. A new family of serine-derived chiral bisoxazolines with ancillary coordination sites were identified as optimal ligands.

Full text of DOI:10.1021/jacs.9b03296

Communication
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Cite This: J. Am. Chem. Soc. XXXX, XXX, XXX−XXX
New Bisoxazoline Ligands Enable Enantioselective Electrocatalytic
Cyanofunctionalization of Vinylarenes
Niankai Fu,† Lu Song,† Jinjian Liu, Yifan Shen, Juno C. Siu, and Song Lin*
Department of Chemistry and Chemical Biology, Cornell University, Ithaca, New York 14853, United States
S
* Supporting Information
Scheme 1. Mechanistic Working Hypothesis
ABSTRACT: In contrast to the rapid growth of synthetic
electrochemistry in recent years, enantioselective catalytic
methods powered by electricity remain rare. In this work,
we report the development of a highly enantioselective
method for the electrochemical cyanophosphinoylation of
vinylarenes. A new family of serine-derived chiral
bisoxazolines with ancillary coordination sites were
identified as optimal ligands.
wing to the prevalence of CC bonds in feedstock
Ochemicals and synthetic intermediates, the heterodifunc-
tionalization of alkenes provides an efficient strategy for rapidly
increasing the complexity of molecules in organic synthesis.1 In
this context, enantioselective methods that provide optically
active compounds are particularly valuable in synthetic and
medicinal applications.2 We3 and others4 have recently
demonstrated electrocatalysis as a viable and potentially general
approach for the difunctionalization of alkenes. Gifted by the
many unique attributes of electrochemistry,5 these reactions are
frequently highly efficient, selective, operationally simple, and
environmentally friendly. Despite these advances, electro-
synthetic methods that enable asymmetric alkene functionaliza-
tion remain elusive.6 In this report, we describe our development
of highly enantioselective cyanophosphinoylation of alkenes
In the envisioned transformation, a secondary phosphine
through the rational design of ligands and optimization of
oxide11 is oxidized on the anode to form the corresponding P-
electrolysis conditions.
In our previous studies, we have demonstrated the use of
centered radical (Scheme 1A, X•).12 This step can be direct or
mediated by a catalyst. Meanwhile, CN− is converted to CN• in
anodically coupled electrolysis (Scheme 1A) for the
the form of a metal−cyano complex (catOX−Y). In this context,
chlorotrifluoromethylation7 and chloroalkylation8 of alkenes.
it has been established that CuII−CN complexes can behave as a
This strategy combines two distinct anodic events occurring in
latent CN• in radical cyanation reactions.13 We envision, upon
parallel to generate two radical intermediates simultaneously.
the addition of the transient P-centered radical to the alkene, the
Regulated by a redox-active catalyst, the addition of these
nascent carbon-centered radical will further react with the
radicals across the alkene π-bond takes place chemo- and
persistent metal−cyano complex to furnish the C−CN bond
and deliver the desired difunctionalized product.14 We reasoned
regioselectively. Given the hypothesized mechanism, it is
plausible to render these processes enantioselective when an
that judicious choice of chiral ligands could render this C−CN
appropriate chiral ligand is used. We set out to investigate this
notion in the context of alkene cyanophosphinoylation by means
of electrochemical generation of cyano- and phosphinoyl radical
equivalents (Scheme 1B). Organophosphorous groups are
prevalent in medicine, agrochemicals, and molecular catalysts;9
nitriles are versatile functional groups in organic synthesis. The
envisioned reaction would install two useful functional handles
to the alkene in a single step, providing unique structural
patterns10 that can be further elaborated to useful products (vide
infra).
bond formation enantioselective, and this hypothesis is
supported in the seminal work by Liu et al. in a series of elegant
chemical cyanation reactions.15
A major challenge of implementing this reaction design lies in
the reconciliation of multiple oxidation and reduction processes
in the same electrochemical system. In particular, the electro-
chemical compatibility and behavior of copper complexes with
Received: March 26, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/jacs.9b03296
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Journal of the American Chemical Society
Communication
common ligand scaffolds that can be readily made chiral [e.g.,
bisoxazoline (BOX), bisphosphine] have not been systemati-
cally studied.16 In addition, for practical reasons, preparative-
scale electrochemical reactions are ideally conducted in
undivided vessels (e.g., common reaction flasks) using feedstock
chemicals as the terminal oxidant or reductant (e.g., H+ as
oxidant). This requirement creates a challenge, as Cu ions are
substantially easier to reduce than H+ and would plate out on the
cathode,17 losing catalytic activity. Therefore, the choice of
solvent, proton source, and ligand is critical.
To further improve the reaction enantioselectivity, we
surveyed a large number (>20) of chiral ligands (e.g., BOX,
PyBOX, BiOX, PyrOX, and BINAP; see Table 1, entry 5 and the
SI), including those that are frequently used in Cu-catalyzed
enantioselective radical reactions (Scheme 2A).19 However, the
Scheme 2. Development of Serine-Derived BOX Ligands
We set out to investigate the feasibility of our reaction design
in the difunctionalization of 4-methoxystyrene (1) using
TMSCN and diphenylphosphine oxide (2) in the presence of
Cu(BOX)-type complexes (Table 1). Using conditions that we
a
Table 1. Reaction Optimization
optimal ee remained 84% (11:1 er). We reasoned substantial
modification to the ligand scaffold would be necessary in order
to break the selectivity ceiling that we encountered.
In a mechanistically related work by Stahl and Liu (Scheme
2A, eq 1),15d the C−CN bond formation via reductive
elimination from a CuIII intermediate was postulated as the
enantioselectivity determining step. In their computational
model, this key CuIII intermediate adopts a pentacoordinated
structure with two CN− bound to the metal in addition to the C-
centered radical and BOX ligand. Analogous pentacoordianted
CuIII complexes have been observed and proposed to undergo
reductive elimination in several other reaction systems.20
Our cyanophosphinoylation reaction differs from the previous
reports by Liu et al.15 primarily in three ways. First, the
phosphine oxide group in the key intermediate leading to
reductive elimination could compete with the ligand or CN− in
binding to the Cu center. Second, DMFa polar solvent that is
used to ensure high solution conductivitycould also
potentially replace a CN− ligand in the cyanation transition
state.21 Finally, the transition state is considerably bulkier owing
to the pendant phosphine oxide group.22 All these factors could
result in a less organized transition structure and induce
unselective reaction pathways.
The above analysis led us to propose that the introduction of
an ancillary ligand (e.g., an ester group) to the BOX scaffold
would further stabilize the putative pentacoordinated CuIII
complex prior to reductive elimination (Scheme 2B). This
modification would also increase the rigidity of the transition
state and improve the stereochemical fidelity of the cyanation
process. Moreover, we hypothesize that this multidentate ligand
will further stabilize the Cu catalyst against cathodic
a
Reaction conditions: 1 (0.2 mmol, 1 equiv), 2 (1.5 equiv), TMSCN
(2.0 equiv), Cu(OTf)2 (3 mol %), ligand (6 mol %), electrolyte (2.0
equiv, 0.1 M), [H+] (2.5 equiv), solvent (4.0 mL), C felt anode, Pt
cathode, undivided cell, constant current i = 3 mA, corresponding to
b
anodic potential of 165−185 mV vs Fc0/+
.
Based on geometrical
surface area.
previously established for electrochemical alkene difunctional-
ization in combination with Cu(L4), no desired product 3 was
observed (entry 1). The Pt cathode was visibly covered with
metallic Cu postelectrolysis. A survey of polar solvents that are
ideal for electrochemistry revealed that DMF is optimal,
providing 3 in 20% yield with 79% ee (entry 2). However, the
Cu catalyst was again irreversibly reduced on Pt and the alkene
was fully consumed to form various side products. Replacing
HOAc with trifluoroethanol (TFE) as the proton source
provided a solution to the product selectivity issue (entry 3).
Although the reaction resulted in marginally lower yield and ee,
little side product was observed and the remaining styrene was
recovered. Finally, screening different electrolytes led to the
discovery of the optimal conditions using ligand L4, providing 3
in 51% yield with 84% ee after passing 2 F of charge (entry 4).18
B
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Communication
a
demetalation and present a cationic intermediate (I) that is
more susceptible to reductive elimination.23
Scheme 3. Substrate Scope
Accordingly, we synthesized a series of bisoxazoline ligands
with pendant ester groups derived from serine (sBOX). To the
best of our knowledge, these ester-substituted BOX ligands have
not been studied in asymmetric catalysis.24 These ligands were
then tested in the model reaction under otherwise identical
conditions, and the difunctionalization product (3) was isolated
in good yield and substantially improved ee (Scheme 3A). In
particular, sBOX(iPr) and sBOX(tBu) provided 94% ee (32:1
er) and 95% ee (39:1 er), respectively. We also tested several
other substituted styrenes, and sBOX outperformed L4 across
the board (Scheme 3B).
Owing to the ease of synthesis,25 sBOX(iPr) was chosen
instead of sBOX(tBu) to study the substrate scope. Styrenes with
a variety of substituents proved to be suitable substrates. In
particular, functionalities that are potentially sensitive to
chemical oxidation, such as aldehyde (21) and sulfide (24),
were preserved under the electrolysis conditions. These
functional groups have not been shown to be compatible with
previously reported cyanation conditions using chemical
10
oxidants, such as Mn(OAc)3 (see SI) and N-fluorobenzene-
sulfonimide.15 Benzyl chloride (27), which could undergo
nucleophilic substitution by CN−, was also tolerated. Notably, a
variety of electron-rich and electron-deficient N-heterocycles
(28, 29, 30, 31) were converted to the corresponding products
in high yield with excellent enantioselectivity. Substituted diaryl
phosphine oxides took part in the difunctionalization smoothly,
providing 32 and 33 with high ee. Dibutyl phosphine oxide also
reacted (34) at elevated temperature (22 °C) to achieve
synthetically useful yield and ee. Introduction of the phosphine
oxide group significantly increases the crystallinity of the
product, whose enantiomeric excess can be upgraded readily
via ether washes with very little mass loss (e.g., 26, 28). The
current reaction conditions are not applicable to substrates that
are intrinsically challenging to Cu-catalyzed cyanofunctionaliza-
tion reactions,10,15 such as dialkylphosphites (no desired
product) and aliphatic alkenes (low enantioselectivity; see SI).
Finally, we demonstrated the synthesis of 3 using ElectraSyn 2.0
instead of our custom-made electrochemical cell and obtained
similar results (see SI).
We also extended this electrochemical protocol to the
cyanosulfinylation of vinylarenes using sulfinic acids as
nucleophiles to furnish product 35−38 in high efficiency and
selectivity. To balance the pH of the medium and ensure the
facile generation of sulfinyl radical, pyridine was added to the
reaction.
The difunctionalized products contain two newly installed
groups, granting access to various structurally diverse molecules
upon further synthetic elaborations. For instance, thiourea-
derived phosphine (39),26 Schiff-based-derived phosphine
oxide (40),27 and aminophosphine (41)28 constitute bifunc-
tional scaffolds that resemble catalysts currently used in
asymmetric synthesis (Scheme 4).
Finally, we propose an electrocatalytic cycle based on
anodically coupled electrolysis (Figure 1A). Cyclic voltammetry
(CV) data showed that the oxidation of CuI(sBOX)(OTf)
catalyst to the corresponding CuII complex results in a feature at
around 0.35 V (vs Fc+/0; Figure 1B, black line). Upon the
addition of TMSCN, however, this redox event takes place at a
less positive potential of 0.15 V with an enhanced anodic current
(red line). This result shows that ligand exchange leads to a
complexpresumably CuI(sBOX)(CN)that is both thermo-
a
Reaction conditions: alkene (0.2 mmol, 1 equiv), P source (1.5
equiv), TMSCN (2.0 equiv), Cu(OTf)2 (3 mol %), ligand (6 mol %),
TBABF4 (2.0 equiv, 0.1 M), TFE (2.5 equiv), DMF (4.0 mL), C felt
b
anode, Pt cathode, undivided cell, constant current i = 3 mA. Total
charge = 2 F, reaction time 3.5 h. Total charge = 3−3.5 F, reaction
time 5−6 h (see SI). 2.0 mmol scale. Ee after ether washes. Using
c
d
e
f
C
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Journal of the American Chemical Society
Communication
Scheme 3. continued
p-toluenesulfinic acid or p-Cl-benzenesulfinic acid with pyridine (2
equiv).
a
Scheme 4. Product Derivatization
a
Reaction conditions: (a) CoCl2 (cat.), NaBH4, MeOH, 0 °C, 83%
yield; (b) CeCl3, LiAlH4, THF, 50 °C, 96% yield; (c) 3,5-
Bistrifluoromethylphenyl isothiocyanate, DCM, 42% yield; (d) 3,5-
Di-tert-butylsalicylaldehyde, EtOH, reflux, 55% yield. (e) NiCl2 (cat.),
NaBH4, Boc2O, MeOH, 66% yield.
dynamically and kinetically more favorable to undergo
oxidation. Importantly, the addition of phosphine oxide 2
further augmented the anodic current at 0.15 V (blue line), and
this current improvement is more pronounced with a higher
concentration of 2 (Figure S3). The observation of such
catalytic current is indicative of CuII(sBOX)(CN) being capable
of oxidizing 2 in a catalytic fashion,29 likely resulting in a free P-
centered radical while returning to the CuI state before anodic
reoxidation. The direct oxidation of diphenylphosphine oxide
on a carbon anode proved to be difficult (>0.3 V; see SI). Finally,
we conducted controlled potential electrolysis with a constant
anodic potential of 0.19 V and observed the formation of
product 3 in 94% ee. These data together are consistent with an
electrochemical difunctionalization reaction mediated by a
[CuI/II(sBOX)(CN)]0/+ redox couple.
Upon addition of the nascent P-centered radical to the alkene
to form the C−P bond, the incipient carbon-centered radical
undergoes single-electron oxidative addition to [CuII(sBOX)-
(CN)]+. This event was followed by reductive elimination to
furnish the chiral product. The resultant CuI picks up another
molecule of CN−which becomes easier to oxidize according
to CV databefore being turned over on the anode to CuII. The
combination of appropriate reaction medium, proton donor,
and chelating ligand allows the merger of Cu redox catalysis and
electrochemistry without the necessity for an additional electron
mediator.
Figure 1. (A) Proposed electrocatalytic cycle. (B) Cyclic voltammetry
data.
by functioning as a Lewis base. The mechanism of
enantioinduction by Cu(sBOX) complexes is a current topic
of investigation.
From the perspective of green chemistry, the removal of a
conventional chemical oxidant constitutes another attractive
feature of our protocol. We anticipate that our electrocatalytic
strategy and new bisoxazoline ligands will pave the way for the
discovery of other synthetically useful transformations.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/jacs.9b03296.
■
S
Mechanism-informed ligand design enabled optimization of
the enantioselectivity of the electrocatalytic difunctionalization
reaction. In our aforementioned working hypothesis, an ester
group in sBOX serves as an ancillary ligand to rigidify the key
reduction elimination transition state toward high levels of
enantioinduction. It is unlikely that these second-sphere groups
provide merely steric repulsions to dictate the reaction
enantioselectivity, as the ester groups are virtually planar, less
Procedures and characterization data (PDF)
AUTHOR INFORMATION
Corresponding Author
*songlin@cornell.edu
■
i
ORCID
bulky, and more flexible than the Pr group in ligand L4.
Juno C. Siu: 0000-0003-4675-5399
Song Lin: 0000-0002-8880-6476
However, it is also possible that the ester groups exert
electrostatic stabilization of the major reaction transition state
D
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Journal of the American Chemical Society
Communication
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Author Contributions
†N.F. and L.S. contributed equally to the work.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support was provided by Cornell University and
NIGMS (R01GM130928). This study made use of the NMR
facility supported by the NSF (CHE-1531632). We thank IKA
for the donation of ElectraSyn 2.0 and Dr. Scott McCann and
Gregory Sauer for constructive discussion.
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(14) The regioselectivity of the addition steps are governed by the
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(16) For examples of Cu-catalyzed electrochemical reactions under
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C−H Amination of Arenes with Secondary Amines. J. Am. Chem. Soc.
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(18) The electrolyte may affect the catalyst structure and the
electrokinetics. At this point, we do not have an explanation for this ee-
dependence on the electrolyte.
(19) For examples, see: (a) Zhu, R.; Buchwald, S. L. Versatile
Enantioselective Synthesis of Functionalized Lactones via Copper-
Catalyzed Radical Oxyfunctionalization of Alkenes. J. Am. Chem. Soc.
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Catalyzed Asymmetric Oxytrifluoromethylation of Alkenes. Angew.
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(20) For reports that propose pentacoordianted Cu intermediates,
see: (a) Addison, A. W.; Burke, P. J.; Henrick, K.; Rao, T. N.; Sinn, E.
Pentacoordinate copper complexes of nitrogen-sulfur donors: struc-
tural chemistry of two complexes of bis(2-(2-benzimidazolyl)ethyl)
sulfide with the sulfur alternatively in equatorial and axial coordination
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Parella, T.; Costas, M.; Stahl, S. S.; Ribas, X. Direct observation of CuI/
CuIII redox steps relevant to Ullmann-type coupling reactions. Chem.
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Arylboronate Esters. Identification of a Copper(III) Fluoride Complex.
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(21) DMF has been shown to provide lower ee in Cu radical catalysis
with BOX-type ligands compared with nonpolar solvents. See: Sha, W.;
Deng, L.; Ni, S.; Mei, H.; Han, J.; Pan, Y. Merging Photoredox and
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(22) Indeed, large tert-leucine-derived BOX ligands consistently
perform poorly in comparison to valine derivatives (e.g., 84% ee with 4
vs 50% ee with 5, 66% ee with 11 vs 12% ee with 12). See SI.
(23) It has been shown that reductive elimination is favored from
cationic organometallic complexes involving metals other than Cu. For
examples, see: (a) Furuya, T.; Benitez, D.; Tkatchouk, E.; Strom, A. E.;
Tang, P.; Goddard, W. A., III; Ritter, T. Mechanism of C−F Reductive
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(24) Although serine-derived BOX ligands have not been used in
enantioselective catalysis, they have been used as intermediates for the
synthesis of alcohol-substituted BOX ligands. For an example, see:
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Enantioselective Desymmetrization of Donor−Acceptor meso-Diami-
nocyclopropanes. Angew. Chem., Int. Ed. 2018, 57, 5120−5123.
(25) The synthesis of sBOX(iPr) requires three steps from
commercially available reactants whereas that of sBOX(tBu) requires
five steps. See SI.
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(27) For use of chiral Schiff base-derived phosphines and phosphine
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precursor could also be readily elaborated to peptide-derived phophines
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F
DOI: 10.1021/jacs.9b03296
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX