Dual electrocatalysis enables enantioselective hydrocyanation of conjugated alkenes

Article abstract of DOI:10.1038/s41557-020-0469-5

Chiral nitriles and their derivatives are prevalent in pharmaceuticals and bioactive compounds. Enantioselective alkene hydrocyanation represents a convenient and efficient approach for synthesizing these molecules. However, a generally applicable method featuring a broad substrate scope and high functional group tolerance remains elusive. Here, we address this long-standing synthetic problem using dual electrocatalysis. Using this strategy, we leverage electrochemistry to seamlessly combine two canonical radical reactions—cobalt-mediated hydrogen-atom transfer and copper-promoted radical cyanation—to accomplish highly enantioselective hydrocyanation without the need for stoichiometric oxidants. We also harness electrochemistry’s unique feature of precise potential control to optimize the chemoselectivity of challenging substrates. Computational analysis uncovers the origin of enantio-induction, for which the chiral catalyst imparts a combination of attractive and repulsive non-covalent interactions to direct the enantio-determining C–CN bond formation. This work demonstrates the power of electrochemistry in accessing new chemical space and providing solutions to pertinent challenges in synthetic chemistry. [Figure not available: see fulltext.]

Full text of DOI:10.1038/s41557-020-0469-5

Articles
https://doi.org/10.1038/s41557-020-0469-5
Dual electrocatalysis enables enantioselective
hydrocyanation of conjugated alkenes
Lu Song1, Niankai Fu1, Brian G. Ernst1, Wai Hang Leeꢀ ꢀ1, Michael O. Frederick2,
1
ꢀ✉
1
ꢀ✉
and Song Linꢀ ꢀ
Robert A. DiStasio Jr.
Chiral nitriles and their derivatives are prevalent in pharmaceuticals and bioactive compounds. Enantioselective alkene
hydrocyanation represents a convenient and efficient approach for synthesizing these molecules. However, a generally
applicable method featuring a broad substrate scope and high functional group tolerance remains elusive. Here, we address
this long-standing synthetic problem using dual electrocatalysis. Using this strategy, we leverage electrochemistry to
seamlessly combine two canonical radical reactions—cobalt-mediated hydrogen-atom transfer and copper-promoted radi-
cal cyanation—to accomplish highly enantioselective hydrocyanation without the need for stoichiometric oxidants. We also
harness electrochemistry’s unique feature of precise potential control to optimize the chemoselectivity of challenging sub-
strates. Computational analysis uncovers the origin of enantio-induction, for which the chiral catalyst imparts a combina-
tion of attractive and repulsive non-covalent interactions to direct the enantio-determining C–CN bond formation. This
work demonstrates the power of electrochemistry in accessing new chemical space and providing solutions to pertinent
challenges in synthetic chemistry.
lkene hydrocyanation, in which H and CN groups are added specific monofunctionalized product in one step from the alkene
across a C=C π-bond, is a highly useful transformation1–4, as precursor, and are therefore complementary to difunctionalization
A
it provides versatile nitriles that are key intermediates in the reactions in the context of target-oriented synthesis. Achieving
synthesis of polymers, agrochemicals, cosmetics and pharmaceuti- this reaction enantioselectively would further increase its synthetic
cals (Fig. 1a)5. This reaction is used in the industrial production of value and grant access to valuable chiral targets for applications in
adiponitrile on a million-tonne annual scale6 and has been explored organic synthesis and medicinal chemistry. Early studies in electro-
by scientists at DuPont in the synthesis of naproxen, a top-selling organic synthesis demonstrated the feasibility of electrochemical
anti-inflammatory medicine7–9. The development of a general cat- hydrofunctionalization of alkenes. However, known examples are
alytic alkene hydrocyanation method with broad substrate scope, primarily limited to intramolecular cyclizations25 or reactions using
precise chemoselectivity and high stereochemical control would activated alkenes (for example, Michael acceptors)26 with limited
have a substantial impact on synthetic organic chemistry across examples of intermolecular hydrofunctionalization of unactivated
both academia and industry. Despite extensive studies on the enan- alkenes27. In addition, no enantioselective variants are currently
tioselective hydrocyanation of polar π-bonds (for example, C=O available. In general, electrosynthetic methods that enable asym-
and C=N)10, analogous methods for the hydrocyanation of alkenes metric alkene functionalization remain elusive28–30. Against this
remain underdeveloped11. Following early examples of highly enan- backdrop, we describe an electrochemical approach for the enan-
tioselective hydrocyanation of 2-methoxy-6-vinylnaphthalene by tioselective hydrocyanation of conjugated alkenes powered by a
RajanBabu et al. in the context of naproxen synthesis7–9, seminal Co/Cu dual electrocatalytic process.
contributions have been made using transition metal catalysis (for
example, Ni catalysis; Fig. 1b)12–17. To date, however, a general cata- Results and discussion
lytic approach that meets the criteria of both broad reaction scope Reaction design. Achieving the desired hydrocyanation using our
and high enantioselectivity remains elusive. In particular, internal electrocatalytic strategy would require the parallel generation of two
alkenes, which would lead to a substantially wider range of useful open-shell species that serve as H• and CN• equivalents. Towards
products, have proven to be challenging substrates.
this goal, we envisioned combining two metal-mediated elemen-
Recently, we have established electrocatalysis18–21 as a broadly tary radical reactions in an anodically coupled electrocatalytic sys-
applicable strategy for the difunctionalization of alkenes22. This tem (Fig. 2a). In the proposed catalytic cycle, [CoIII]–H (formally),
approach merges the electrochemical generation of radical inter- generated from a CoIII precursor and a hydrosilane31–35, reacts with
mediates with catalyst-controlled radical addition to the alkene. an alkene substrate via hydrogen-atom transfer (HAT) to pro-
Specifically, we devised anodically coupled electrolysis—a pro- duce carbon-centred radical I36–38. This intermediate then enters
cess that combines two anodic events to form two distinct radi- the cyanation cycle and undergoes single-electron oxidative addi-
cal intermediates—for the synthesis of a diverse suite of vicinally tion to [CuII]–CN to form species II, a formally CuIII intermediate.
heterodifunctionalized structures23,24
. Further applying elec- Subsequent reductive elimination completes the hydrocyanation
trocatalysis to the hydrofunctionalization of alkenes, such as reaction39–41
.
hydrocyanation, would substantially expand the scope of electro-
This reaction design has garnered inspiration from two key dis-
synthesis. Such transformations would enable direct access to a coveries in the area of metal-mediated radical chemistry. For one,
1Department of Chemistry and Chemical Biology, Cornell University, Ithaca, NY, USA. 2Small Molecule Design and Development, Eli Lilly and Company,
✉
Indianapolis, IN, USA. e-mail: distasio@cornell.edu; songlin@cornell.edu
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HAT-initiated alkene functionalization could intercept a second
organometallic cycle in the context of Co/Ni-catalysed hydroary-
lation42. Nevertheless, there have been very few applications of
MHAT to asymmetric catalysis43, and no study has been performed
to date in the context of MHAT-mediated electrocatalysis. Secondly,
our mechanistic design was also inspired by recent advances in
enantioselective Cu-catalysed radical cyanation. For example,
Liu reported a series of elegant methods for the enantioselective
cyanofunctionalization of styrenes promoted by chemical oxi-
dants40. Harnessing this reactivity, we have recently established the
viabilityofCu-mediatedasymmetricelectrocatalysisinthecontextof
cyanophosphinoylation of alkenes by replacing chemical oxidants44
with an anode45. However, the scope of this cyanophosphinoylation
reaction was limited to terminal styrenes. More importantly, Cu
catalysis alone is not amenable to the development of a highly
enantioselective hydrocyanation reaction, which is a synthetically
more valuable transformation. In this work, we investigate a dual
catalytic strategy that harnesses the synergistic combination of Co
HAT and Cu cyanation, thereby providing a unique solution to this
synthetic challenge.
The desired hydrocyanation reaction is an overall oxidative
transformation, which requires the turnover of both catalysts via
a pair of single-electron oxidation events to return the resultant
CoII and CuI species back to their reactive CoIII and CuII oxida-
tion states (Fig. 2a). The key to successfully achieving this reac-
tion therefore relies on the identification of oxidative conditions
that seamlessly accommodate both the Co HAT and Cu cyanation
cycles. We note that the attributes of electrochemistry render it
uniquely capable of facilitating the merger of these two catalytic
processes into a broadly useful hydrocyanation protocol. On one
hand, Co-catalysed hydrofunctionalization can encounter che-
moselectivity issues with styrene-type substrates (vide infra),
particularly in the presence of an oxidant; this is likely due to the
formation of a benzylic radical that is susceptible to over-oxidation
to a benzyl cation46. On the other hand, Cu-catalysed cyanation
requires a potent chemical oxidant39,40, which can also limit the
reaction scope to substrates lacking oxidatively labile functional
groups. By contrast, electrochemical strategies allow one to dial
in a minimally sufficient potential, thereby circumventing the
need for stoichiometric oxidants and addressing the incom-
patibility issues potentially associated with our Co/Cu dual
catalytic process.
a
Ph
NH
Me
O
Me
CO2H
N
N
O
MeO
Me
Saredutant
Naproxen
(anti-depressant)
(anti-inflammatory)
Cl
Cl
O
N
N
CN
N
N
H
Palonosetron
AMD7270
(treating chemotherapy-induced
emesis)
(HIV-1 replication inhibitor)
N
N
H
Cl
CF3
Me
N
O
N
OMe
Me
N
O
F
H
N
N
H
O
HO
O
Duocarmycin analogue
(inhibitor of aldehyde dehydrogenase
in lung cancer cells)
Tetflupyrolimet
(herbicide)
b
CN
H
H
X*
CN
H
X*
Chiral ion pair
c
NC
L*
H
L*
[Ni] CN
CN
[Ni]
H
H
d
CN
H
[Co]
H
[Cu] CN
H
Reaction discovery and development. We set out to evaluate
various combinations of Co and Cu catalysts. The electrochemical
properties of many Co complexes have been well documented47.
However, the electrochemical compatibility and behaviour of Cu
complexes with common chiral ligands are largely unknown. In
addition, Cu ions are highly susceptible to electroplating on the
cathode (complete reduction of Cu(OTf)2 observed at approxi-
mately –0.5 V versus ferrocenium/ferrocene, Fc+/0, in dimethyl-
formamide (DMF); see Supplementary Fig. 8). In an undivided
electrochemical cell (for example, a standard laboratory flask), an
ideal vessel for preparative-scale electrochemical reactions, Cu
complexes could be readily reduced at the cathode and lose cata-
lytic activity48. Through systematic optimization, we found that
Co(salen) complex 3 (0.5 mol%) and Cu(OTf)2 (5 mol%) together
with bisoxazoline (BOX)-type ligands (5–7; 10 mol%) in the pres-
ence of PhSiH3 and trimethylsilyl cyanide (TMSCN) promoted
the conversion of 4-tert-butylstyrene (1) to the desired product
(2) in good yield and moderate enantioselectivity (50–72% e.e.;
Fig. 1 | Enantioselective hydrocyanation: synthetic significance and
proposed strategy. a, Arylpropionitriles and derivatives in pharmaceuticals
and agrochemicals. b–d, Strategies for enantioselective hydrocyanation
of alkenes. A challenge for the carbocation pathway (b) is that
enantio-induction with benzyl cations is difficult. There are no precedents,
despite extensive use of this strategy in C=X (X = O, N) hydrocyanation10.
Challenges for the Ni hydride pathway (c) are the limited scope and the
fact that the reaction yield and selectivity are highly dependent on the
structure and electronic properties of the alkene. There are precedents to
this pathway7–9,12–15. Features of the electrochemical radical pathway (d) in
this work are its broad scope, high enantioselectivity, high functional group
tolerance, electrochemical control of chemoselectivity and mechanistic
information. Asterisks in b–d denote chiral groups or ligands.
metal hydride hydrogen-atom transfer (MHAT) has recently been Fig. 2b). Cyclic voltammetry studies revealed that both the BOX
established as a versatile approach for the hydrofunctionalization ligand and CN– are important in keeping the Cu catalyst in solu-
of alkenes31. Directly related to this work, Carreira reported a race- tion presumably through the formation of [Cu(BOX)(CN)n]-type
mic version of Co-catalysed alkene hydrocyanation using TsCN complexes, avoiding detrimental cathodic deposition during elec-
as the CN source3. Recently, Shenvi showed for the first time that trolysis (see Supplementary Fig. 9). In addition, the combination
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a
2H+
of Pt as the cathode and HOAc as the terminal oxidant is impor-
tant to ensure facile proton reduction at a relatively low overpo-
tential, which outcompetes the undesired Cu reduction.
2e–
+ –
Pt cathode
H2
To further optimize enantioselectivity, we surveyed a catalogue
of chiral bidentate N,N- and P,P-ligands, including several that are
known to be excellent Cu ligands for enantioselective Lewis acid49
or radical catalysis39,40,50,51. However, the optimal e.e. could not be
improved above 72% (ligand 7). During our reaction optimization,
we discovered that serine-derived bisoxazolines (sBOXs; for exam-
ple, 4) are excellent ligands in the desired hydrocyanation reaction.
These ligands are readily prepared from serine52, and were recently
shown by us to be effective ligands in the cyanophosphinoylation
reaction as well45. As shown in Fig. 2b, the use of ligand 4 drasti-
cally improved the reaction enantioselectivity to 91% e.e. and also
increased the yield to 79%. Using computational methods, we show
that such high reaction enantioselectivity arises from a complex
interplay between attractive and repulsive non-covalent interac-
tions due to the second-sphere ester groups in these sBOX ligands
(vide infra).
CoII
R
e–
Substrate
Anodic cycle 1: HAT
CoIII
CoIII
H
R3Si
H
H
(I)
R
uIII
]
[C
CN
H
CN–
CuI
CuI
CN
R
(II)
e–
A number of control experiments serve to highlight the impor-
tance of each component of our reaction system. For example, using
MeCN instead of DMF as the solvent, LiClO4 instead of tetrabutyl-
ammonium tetrafluoroborate (TBABF4) as the electrolyte or EtOH
instead of HOAc as the proton source led to decreased product
yield (Fig. 2b). Notably, the product was also formed in substan-
tially lower e.e. in the presence of LiClO4. Previous work showed
that the identity of the electrolyte can substantially affect the polar-
ity of the electrical double layer (EDL)53. As such, we hypothesize
that TBABF4 creates a much less polar EDL on the anode than
LiClO4, which is responsible for the improved enantioselectivity.
When Co loading was increased from 0.5 to 2mol%, the yield of
2 was dramatically decreased and a large amount of hydrogenated
side product was observed38. This result highlights the importance
of balancing the rates of the HAT and cyanation events to ensure
optimal product selectivity. Finally, the reaction requires both
Cu and Co to operate, as excluding either catalyst led to minimal
conversion to the hydrocyanation product.
Anodic cycle 2: cyanation
CN
CuII
CN
H
*
R
C anode
Product
CN
b
[Co] 3 (0.5 mol%), Cu(OTf)2 (5 mol%)
Ligand 4–7 (10 mol%), PhSiH3, TMSCN
Ar
H
TBABF4, HOAc/DMF, 0 °C, 10 h
Ar
C(+)/Pt(–), Ucell = 2.3 Va
1
2
(Ar = 4-tBuPh)
sBOX(tBu)
N
O
N
O
O
O
Co
+
N
N
tBu
tBu
O
O
OtBu
tBuO
tBu
tBu
Reaction scope and application. In addition to representing a
conceptual advance, our electrochemical hydrocyanation is also
synthetically valuable and provides a complementary route to
existing methods for the synthesis of chiral nitriles. Under optimal
conditions, a variety of vinylarenes underwent hydrocyanation to
furnish desired arylpropionitriles with excellent enantioselectiv-
ity (Table 1). The efficiency of the transformation was found to be
relatively independent of the electronic properties of the aryl sub-
stituents. Importantly, the very mild reaction conditions imparted
by the combination of electrochemistry and a radical mechanism
made accessible a broad scope of enantio-enriched nitriles with a
diverse range of functional groups. In particular, functionalities that
are susceptible to oxidative degradation under chemical conditions,
such as electron-rich arenes (for example, 8, 15, 20), sulfides (11)
and aldehydes (13), can be readily engaged in the hydrocyanation.
Furthermore, groups including benzyl chlorides (12), aryl halides
(9, 25) and aryl boronates (17), which might induce catalyst pro-
miscuity under Ni-promoted conditions, were well tolerated in our
reaction. Alkenes with various heterocycles (20–23, 25) also proved
excellent substrates. The scalability of the reaction was demon-
strated in the synthesis of products 2 and 15 on 2–5mmol scales
(a 10–25 times scale-up), which were isolated in comparable but
marginally decreased yield and e.e. We attribute the reduction in
yield and e.e. to inefficient mass and heat transport due to the het-
erogeneous nature of electrode reactions, which may be addressed
via reactor engineering.
4: 79% yield,b 91% e.e.
3
Variation from optimal conditions:
MeCN as solvent:
LiClO4 as electrolyte:
EtOH as H+ source:
2 mol% [Co] 3:
31% yield, 88% e.e.
59% yield, 66% e.e.
50% yield, 84% e.e.
37% yield, 84% e.e.
8% yield, 83% e.e.
<5% yield
Without Co:
Without Cu:
Other commonly used BOX ligands:
O
N
O
O
O
O
O
N
N
N
N
N
iPr
Bn
iPr
Bn
5: 67% yield
–62% e.e.
6: 46% yield
–50% e.e.
7: 73% yield
72% e.e.
Fig. 2 | Reaction design, discovery and optimization. a, Anodically coupled
dual electrocatalysis provides an effective strategy to couple two distinct
radical catalytic cycles for alkene hydrocyanation. b, Optimization of the
reaction conditions and control experiments. Yields were determined by
1H NMR. aUcell, cell voltage applied between the cathode and anode;
U
cellꢀ=ꢀ2.3ꢀV corresponds to ~0.24ꢀV versus Fc+/0 anodic potential (Eanode
)
and gives ~2ꢀmA initial current. bIsolated yield. e.e., enantiomeric excess.
reported enantioselective hydrocyanation reactions due to their
Our reaction is also applicable to internal alkenylarenes low reactivity13. Our protocol shows very broad substrate gener-
(Table 1), which are typically challenging substrates in previously ality, furnishing products with a variety of synthetically useful
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Table 1 | Reaction scope
Terminal alkenes:
CN
CN
CN
CN
CN
CN
CN
OHC
Me
Me
Me
Me
Me
Me
Me
Cl
tBu
2, 79%, 91% e.e.
MeO
8, 64%, 90% e.e.a
Br
9, 69%, 84% e.e.
MeS
10, 76%, 84% e.e.
11, 69%, 86% e.e.
12, 78%, 86% e.e.
13, 82%, 81% e.e.
5 mmol scale: 55%, 85% e.e.
CN
CN
CN
Me
CN
Me
CN
O
CN
Me
Me
Me
Me
Me
MeO
Me
AcHN
MeO
Me
pinB
17, 82%, 92% e.e.
CO2Me
14, 90%, 93% e.e.
15, 81%, 91% e.e.
16, 95%, 90% e.e.
18, 79%, 85% e.e.
19, 57%, 86% e.e.
2 mmol scale: 71%, 90% e.e.
CN
NC
Me
CN
Me
CN
CN
Me
CN
CN
Me
Me
H
N
Me
Me
Me
Me
O
H
N
N
Me
Ts
N
Me
Me
N
Cl
Ts
Me
O
20, 71%, 87% e.e.a
21, 74%, 92% e.e.
22, 65%, 85% e.e.
23, 86%, 80% e.e.
24, 66%, 88% e.e.
25, 78%, 85% e.e.
26, 88%, 86% d.e.
Internal alkenes:
CN
CN
CN
CN
CN
Ph
CN
Me
Ph
OH
Cl
OBz
32, 51%, 95% e.e.b
(2.7:1 r.r., minor: 88% e.e.)
27, 81%, 88% e.e.
28, 88%, 91% e.e.
29, 78%, 91% e.e.
30, 75%, 91% e.e.
31, 63%, 93% e.e.
CN
CN
CN
CN
CN
CN
Br
CN
O
B
OAc
Ph
Ph
O
Ph
33, 49%, 95% e.e.c
(2:1 r.r., minor: 55% e.e.)
34, 61%, 94% e.e.
35, 65%, 85% e.e.
36, 70%, 80% e.e.
37, 69%, 90% e.e.
38, 71%, 95% e.e.
O
Ph
CN
O
H
CN
O
CN
O
CN
O
CN
O
CN
O
CF3
CN
Ph
H
Ph
OMe
Ph
Me
Ph
Ph
MeO
N
Me
O
42, 45%, 91% e.e.b
39, 82%, 94% e.e.
40, 66%, 95% e.e.
41, 32%, 88% e.e.
43, 89%, 91% e.e.
44, 76%, 93% d.e.
Other conjugated alkenes:
Dienes and enynes:
CN
NC
Me
CN
Me
CN
Ph
CN
Me
Me
CN
Ph
Me
Ph
Me
Me
Me
Me
Me
C5H11
MeO
45, 73%, 86% e.e.
46, 63%, 84% e.e.
47, 64%, 82% e.e.
48, 68% (Z/E = 1:1)
Z = 71% e.e., E = 66% e.e.
49, 68%, 93% e.e.
50, 68%, 76% e.e.
Allene:
Radical probe:
CN
CN
CN
or
Me
CN
Ph
Ph
Me
Me
55, 86%, 82% e.e.
51
54
52, 64%
(condition A)d
53, 59%, 91% e.e.
(condition B)e
Conditions: alkene (0.2ꢀmmol, 1 equiv.), PhSiH3 (1.1 equiv.), TMSCN (2.0 equiv.), Co 3 (0.5ꢀmol%), Cu(OTf)2 (5ꢀmol%), ligand 4 (10ꢀmol%), TBABF4 (2.0 equiv.), HOAc (5.0 equiv.), DMF (4.0ꢀml), C anode, Pt
cathode, undivided cell, 0ꢀ°C and Ucellꢀ=ꢀ2.3ꢀV. Isolated yields are reported, unless otherwise noted. aOptimal yield obtained at Ucellꢀ=ꢀ1.8ꢀV (see Fig. 4a and corresponding discussion). bWith 1ꢀmol% Co 3. cWith
2ꢀmol% Co 3. dCondition A: with 1.5 equiv. TMSCN, 1.1 equiv. PhSiH3; yield determined by 1H NMR. eCondition B: with 4.0 equiv. TMSCN, 2.2 equiv. PhSiH3. r.r., regiomeric ratio; d.e., diastereomeric excess.
functional handles (28, 29, 34, 38) and N-heterocyclic motifs (43). can be used directly in this reaction. Both electron-rich (37) and
Since the stereochemistry of the starting alkene does not affect electron-deficient (39–44) alkenes proved suitable substrates.
the yield or enantioselectivity, a mixture of E and Z isomers In particular, hydrocyanation was achieved for cinnamoyl-type
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a
Derivatization products
CO2Me
Me
Analogous drugs
CO2H
Me
CN
HCl, MeOH
80 °C
Me
MeO
MeO
MeO
15, 90% e.e.
56, 62%, 90% e.e.
(R)-naproxen
b
(1) CoCl2, NaBH4, MeOH
(2) 2-PyCO2H, EDC
DMAP, DCM
Me
CN
Cl
Me
N
O
HO
(3) Pd(OAc)2, PhI(OAc)2
Toluene, 60 °C
N
O
MeO
MeO
2-Py
R
15, 90% e.e.
57, 62%, 90% e.e.
(over three steps)
Duocarmycin analogue
(R: see Fig. 1a)
c
O
O
CN
CoCl2, NaBH4, MeOH
0 °C to 22 °C to reflux
N
N
NH
Me
H
CO2Me
Me
18, 85% e.e.
58, 81%, 87% e.e.
Palonosetron
Fig. 3 | Product derivatization. a, Product 15 is transformed to naproxen methyl ester 56 (analogue of naproxen) via methanolysis. b, Product 15 is
transformed to benzoindoline 57 (analogue of duocarmycin) via reduction followed by C–H amination. c, Product 18 is transformed to dihydroisoquinolone
58 (analogue of palonosetron) via reduction and subsequent amide formation. Detailed experimental procedures can be found in Section 6 of
the Supplementary Information. DMAP, 4-(dimethylamino)pyridine; EDC, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride; DCM,
dichloromethane.
structures including esters (39, 43, 44), ketones (40, 41) and
Alkyl nitriles are highly versatile synthetic intermediates that
nitriles (42). These results demonstrate that our reaction can can be readily transformed to a variety of useful functional groups,
serve as a more general alternative to the enantioselective Michael such as aldehydes, alcohols, carboxylic acids, esters, amines and
addition en route to similar products. Considering that numerous heterocycles. Here we showcase the synthetic value of our reaction
bioactive natural products and their synthetic precursors contain products through three examples (Fig. 3). Product 15 was readily
cinnamoyl side chains (for example, taxol, phyllanthocin), our converted to either naproxen methyl ester 56 via methanolysis or
method provides a convenient means to derivatize these com- to benzoindoline 57 via reduction followed by Pd-catalysed C–H
pounds for medicinal chemistry studies.
amination55. Both derivatizations occurred with complete retention
We further extended the scope of our reaction to other types of stereochemistry. Nitrile 18 was subjected to reduction and subse-
of unsaturated substrates (Table 1). For example, dienes were quent cyclization to yield dihydroisoquinolone 58. These products
converted to mono-hydrocyanated products in high efficiency bear structural resemblance to high-value drug molecules, again
and enantioselectivity. In the case of linear dienes (45–49), the highlighting the significance of the enantioselective hydrocyana-
reaction selectively functionalizes the terminal C=C π-bond. tion reaction.
Structurally analogous enynes also reacted chemoselectively in
good e.e. (50). Interestingly, in these transformations, enanti- Electrochemical control of reaction chemoselectivity. A key
oselective Cu-mediated C–CN bond formation is achieved via advantage of electrochemistry is the ability to achieve external
an allyl or propargyl radical species54. Finally, we expanded the control over the electrode potential input. This feature allowed us
reaction scope to allenes. The hydrocyanation of phenylallene to regulate the hydrocyanation chemoselectivity of electron-rich
(51) yielded cinnamyl cyanide (52) as the predominant product. vinylarenes (Fig. 4a). For example, using 3-vinyl-N-Ts-indole as
Based on density functional theory (DFT) calculations, we believe the substrate, under our standard conditions with the application
that this product arose from regioselective HAT at the cen- of a cell voltage of 2.3V (Eanode ≈0.24V versus Fc+/0), we observed
tral allene carbon to form an allyl radical (24.3 kcal mol–1 more full conversion of the alkene but minimal formation of the desired
stable than the corresponding vinyl radical; see Supplementary nitrile 20. Instead, several side products were formed, including
Fig. 13) followed by Cu-promoted regioselective cyanation at those that arose from over-oxidation of the benzyl radical interme-
the primary carbon to maintain the conjugated styrene motif diate56 to the corresponding cation followed by nucleophilic trap-
(4.1 kcal mol–1 lower barrier than cyanation at the benzylic car- ping (for example, formate and ketone products). By lowering the
bon; see Supplementary Fig. 13). This selectivity allowed us to voltage input from 2.3V to 1.8V (Eanode ≈0.08V), we successfully
achieve double hydrocyanation through the use of an excess of suppressed over-oxidation and obtained hydrocyanation product
reagents to generate 1,3-dinitrile 53 with high enantioselectivity. 20 in 71% yield. This principle was also applied to the optimization
A radical rearrangement experiment provided key support for of reactions forming 8 and 59.
the intermediacy of the organic radical species. Exposure of
For comparative purposes, we examined the hydrocyanation of
cyclopropane-derived alkene 54 to the reaction conditions led to alkene 1 under traditional chemical conditions without an electri-
the expected ring opening, furnishing alkene-containing nitrile cal input. None of the chemical oxidants we surveyed promoted
55 in high yield and enantioselectivity.
the reaction with efficiencies or enantioselectivities comparable to
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Stereochemical model. Finally, we enlisted theoretical methods
to elucidate the role played by sBOX ligands in directing the
highly enantioselective Cu-mediated hydrocyanation. A previous
study showed that the radical combination to generate interme-
diate II (Fig. 2) is facile, whereas reductive elimination to con-
struct the C–CN bond is slow and thus enantio-determining39.
Traditionally, BOX-type ligands are thought to induce enantiose-
lectivity through primarily repulsive steric interactions imparted
by the bulky substituents on the oxazoline groups49. Considering
that the ester-derived ligands (4, 60) perform substantially better
than the canonical BOX ligands with various steric profiles (for
example, 5–7), we hypothesized that the ester groups must also
provide attractive interactions with the substrate assembly in the
key C–CN-forming transition state (TS). DFT computations are
fully consistent with this hypothesis (Fig. 5 and Supplementary
Information Section 7). Using the reaction that forms 10 as an
example, the lowest-energy TS structures leading to the major
(R) and minor (S) products (TSR and TSS, respectively) both dis-
play a favourable C–H∙∙∙π interaction between the acidic pro-
ton at the α-position of one ester group and the substrate aryl
group. This attractive non-covalent interaction dictates the TS
geometry by positioning the substrate alkyl group towards the
ester on the opposite half of the catalyst. However, this arrange-
ment causes more severe steric interactions in TSS than TSR. In
addition to having the closest catalyst–substrate contacts (d3
in Fig. 5), these exponentially repulsive steric interactions also
a
NC
CN
Me
CN
Me
Me
N
MeO
Ts
20
8
59
Ucell = 2.3 V: 11%a
Ucell = 1.8 V: 71%b
Ucell = 2.3 V: 45%a
Ucell = 1.8 V: 64%b
Ucell = 2.3 V: <5%a
Ucell = 1.5 V: 52%b
Observed by-products:
O
OCHO
Me
Ar
Me
Ar
b
Co(salen) 3 (0.5 mol%), PhSiH3
Cu(OTf)2 (5 mol%), 60 (10 mol%), TMSCN
CN
H
Ar
Ar
Oxidant, TBABF4, HOAc, DMF, 0 °C
1
2
(Ar = 4-tBuPh)
Entry
1
Oxidant
Conversion (%)a
Yield (%)a
e.e. (%)
Anode
NFSI
92
38
85
78
63
86
50
>95
79
75
8
87
<5
15
24
<5
9
85
c
2
—
3
TBHP
68
63
4
[F+]
c
5
PhI(OAc)2
Mn(OAc)3
Cu(OAc)2
O2 (balloon)
[I+]
—
t
force the bulky Bu-ester group to deviate more substantially
6
40
52
from its optimal planar geometry in TSS (both θ values in Fig.
5), and this broken conjugation further destabilizes the minor TS
(Supplementary Information Section 11). Based on these find-
ings, we further hypothesize that this complex interplay between
attractive and repulsive non-covalent interactions in the TS
determines the reaction enantioselectivity. We note in passing
that this computational analysis refutes our previous hypothesis45
that direct coordination of the ester groups to the Cu centre was
responsible for stabilizing the major TS during enantioselective
C–CN formation.
This stereochemical model is consistent with our experimen-
tal observations. For example, reactions with internal alkenes are
in general more enantioselective than those with terminal alkenes.
This can be explained by the increased steric interactions between
the substrate alkyl group and the catalyst ester group in TSS for the
internal alkenes. In addition, substrates with more electron-rich aryl
groups (for example, 2, 8) in general lead to higher enantioselectiv-
ity than those with electron-deficient groups (for example, 9, 13),
which can be rationalized by an enhanced C–H∙∙∙π interaction with
the aryl group57.
7
15
<5
14
<5
<5
c
8
—
9
62
c
10
11
CAN
—
–
c
Fc+BF4
—
Me
O
O
N
O
N
OTf
Me
O
I
Me
N
F
O
O
OH
OiPr
iPrO
[F+]
[I+]
sBOX(iPr) 60
Fig. 4 | Electrochemical tuning of reaction chemoselectivity
and comparison with chemical methods. a, Reaction yield and
chemoselectivity can be improved by lowering applied potential,
minimizing by-products formation from overoxidation of electron-rich
substrates. aDetermined by 1H NMR. bIsolated yield. b, Control experiments
show that common chemical oxidants in lieu of anodic oxidation cannot
provide same levels of reactivity or enantioselectivity. cNot determined.
NFSI, N-fluorobenzenesulfonimide; TBHP, tert-butyl hydroperoxide; CAN,
ceric ammonium nitrate.
Conclusions
The electrocatalytic hydrocyanation described herein reveals the
unique advantages of harnessing electrochemistry in exploring new
chemical space and developing solutions to challenging synthetic
problems. This new transformation will enhance chemists’ access
to a diverse array of enantio-enriched nitriles. On a fundamental
our protocol (Fig. 4b). In cases where a low yield of 2 was obtained level, the realization of electrochemical hydrofunctionalization and
(9–24%), the enantioselectivity was also substantially lower demonstration of enantioselective electrocatalysis will improve
(40–68%e.e.). This erosion of e.e. is likely a result of a racemic the scope of electrosynthesis and its adoption in modern organic
carbocation pathway caused by over-oxidation of the key benzylic chemistry.
radical intermediate. We note that, although these results could
potentially be improved through extensive optimization of reaction Online content
conditions, such optimization studies would need to address the Any methods, additional references, Nature Research report-
challenges associated with the use of a terminal chemical oxidant. ing summaries, source data, extended data, supplementary infor-
Electrochemistry, with its ability to enable electron transfer with mation, acknowledgements, peer review information; details of
a minimally sufficient potential input, provides an ideal means to author contributions and competing interests; and statements of
circumvent issues with chemical oxidation and harness multiple data and code availability are available at https://doi.org/10.1038/
redox catalytic cycles for productive chemistry.
s41557-020-0469-5.
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TSR
TSS
C1
C1
O1
C2
C2
O1
θ
O2
d1
d1
d2
C3
O2
C3
d3
d2
d3
TSR (major) TSS (minor)
O
O
O
O
O
d1 (Å)
2 (Å)
3 (Å)
2.43
2.25
2.32
172.8
7.4
2.34
2.35
2.16
158.1
16.8
CN
CN
N
d
N
N
N
H
H
O
θ
CH3
O
Cu
Cu
O
d
O
θ
CH3
d1
d1
O
O
O
CN
d
d2
CN
H
2
θC1
(°)
(°)
C
O C
2
H
H
2
3
H
H
H
tBu
CH3
CH3
tBu
H
θO1
C
O C
2
d3
H
2
3
H
H
H
d3
H
H
H
∆∆G‡ (kcal mol–1
)
+1.46
Fig. 5 | Computational stereochemical model. The minor and major TS for the reaction with ligand 4 and styrene (giving product 10) are shown. DFT
models show that the combination of an attractive C–H∙∙∙π interaction between substrate and catalyst in conjunction with a sterically induced structural
distortion of the catalyst determines the reaction enantioselectivity. Numbers in red indicate closest catalyst–substrate contacts or dihedral angles that
substantially deviate from their optimal values.
15. Wilting, J., Janssen, M., Müller, C. & Vogt, D. Te enantioselective step in the
Received: 16 September 2019; Accepted: 21 April 2020;
nickel-catalyzed hydrocyanation of 1,3-cyclohexadiene. J. Am. Chem. Soc.
Published: xx xx xxxx
128, 11374–11375 (2006).
16. Li, X. et al. Asymmetric hydrocyanation of alkenes without HCN.
References
Angew. Chem. Int. Ed. 58, 10928–10931 (2019).
1. Rajanbabu, T. V. Hydrocyanation of alkenes and alkynes. Org. React. 75,
1–73 (2011).
17. Schuppe, A. W., Borrajo-Calleja, G. M. & Buchwald, S. L. Enantioselective olefn
hydrocyanation without cyanide. J. Am. Chem. Soc. 141, 18668–18672 (2019).
18. Francke, R. & Little, R. D. Redox catalysis in organic electrosynthesis: basic
principles and recent developments. Chem. Soc. Rev. 43, 2492–2521 (2014).
19. Jutand, A. Contribution of electrochemistry to organometallic catalysis.
Chem. Rev. 108, 2300–2347 (2008).
2. Nugent, W. A. & McKinney, R. J. Nickel-catalyzed Markovnikov addition of
hydrogen cyanide to olefns. Application to nonsteroidal anti-infammatories.
J. Org. Chem. 50, 5370–5372 (1985).
3. Gaspar, B. & Carreira, E. M. Mild cobalt-catalyzed hydrocyanation of olefns
with tosyl cyanide. Angew. Chem. Int. Ed. 46, 4519–4522 (2007).
4. Fang, X., Yu, P. & Morandi, B. Catalytic reversible alkene-nitrile
interconversion through controllable transfer hydrocyanation. Science 351,
832–836 (2016).
20. Meyer, T. H., Finger, L. H., Gandeepan, P. & Ackermann, L. Resource
economy by metallaelectrocatalysis: merging electrochemistry and C–H
activation. Trends Chem. 1, 63–76 (2019).
21. Yan, M., Kawamata, Y. & Baran, P. S. Synthetic organic electrochemical
methods since 2000: on the verge of a renaissance. Chem. Rev. 117,
113230–113319 (2017).
5. Pollak, P., Romeder, G., Hagedorn, F. & Gelbke, H. Ullman’s Encyclopedia of
Industrial Chemistry 5th edn, Vol. A17 363 (Wiley-VCH, 1985).
6. Tolman, C. A., McKinney, R. J., Seidel, W. C., Druliner, J. D. & Stevens, W. R.
Homogeneous nickel-catalyzed olefn hydrocyanation. Adv. Catal. 33,
1–46 (1985).
22. Fu, N., Sauer, G. S., Saha, A., Loo, A. & Lin, S. Metal-catalyzed
electrochemical diazidation of alkenes. Science 357, 575–579 (2017).
23. Ye, K. et al. Anodically coupled electrolysis for the heterodifunctionalization
of alkenes. J. Am. Chem. Soc. 140, 2438–2441 (2018).
7. RajanBabu, T. V. & Casalnuovo, A. L. Tailored ligands for asymmetric
catalysis. J. Am. Chem. Soc. 114, 6265–6266 (1992).
24. Fu, N. et al. Mn-catalyzed electrochemical chloroalkylation of alkenes.
ACS Catal. 9, 746–754 (2019).
8. RajanBabu, T. V. & Casalnuovo, A. L. Role of electronic asymmetry
in the design of new ligands: the asymmetric hydrocyanation reaction.
J. Am. Chem. Soc. 118, 6325–6326 (1996).
25. Zhu, L. et al. Electrocatalytic generation of amidyl radicals for olefn
hydroamidation: use of solvent efects to enable anilide oxidation. Angew.
Chem. Int. Ed. 55, 2226–2229 (2016).
9. Casalnuovo, A. L., RajanBabu, T. V., Ayers, T. A. & Warren, T. Ligand
electronic efects in asymmetric catalysis: enhanced enantioselectivity in
asymmetric hydrocyanation of vinylarenes. J. Am. Chem. Soc. 116,
9869–9882 (1994).
26. Miranda, J. A., Wade, C. J. & Little, R. D. Indirect electroreductive
cyclization and electrohydrocyclization using catalytic reduced nickel(II)
salen. J. Org. Chem. 70, 8017–8026 (2005).
10. Kurono, N. & Ohkuma, T. Catalytic asymmetric cyanation reactions.
ACS Catal. 6, 989–1023 (2016).
11. Bini, L., Müller, C. & Vogt, D. Ligand development in the Ni-catalyzed
hydrocyanation of alkenes. Chem. Commun. 46, 8325–8334 (2010).
12. Saha, B. & RajanBabu, T. V. Nickel(0)-catalyzed asymmetric hydrocyanation
of 1,3-dienes. Org. Lett. 8, 4657–4659 (2006).
13. Falk, A., Göderz, A.-L. & Schmalz, H.-G. Enantioselective nickel-catalyzed
hydrocyanation of vinylarenes using chiral phosphine–phosphite ligands and
TMS–CN as a source of HCN. Angew. Chem. Int. Ed. 52, 1576–1580 (2013).
14. Falk, A., Cavalieri, A., Nichol, G. S., Vogt, D. & Schmalz, H.-G.
Enantioselective nickel-catalyzed hydrocyanation using chiral phosphine–
phosphite ligands: recent improvements and insights. Adv. Synth. Catal. 357,
3317–3320 (2015).
27. Shono, T. et al. Electroorganic chemistry. 118. Electroreductive intermolecular
coupling of ketones with olefns. J. Org. Chem. 54, 6001–6003 (1989).
28. Lin, Q., Li, L. & Luo, S. Asymmetric electrochemical catalysis. Chem. Eur. J.
25, 10033–10044 (2019).
29. Nguyen, B. H., Redden, A. & Moeller, K. D. Sunlight, electrochemistry, and
sustainable oxidation reactions. Green Chem. 16, 69–72 (2014).
30. Torii, S., Liu, P. & Tanaka, H. Electrochemical Os-catalyzed asymmetric
dihydroxylation of olefns with Sharpless’ ligand. Chem. Lett. 24,
319–320 (1995).
31. Crossley, S. W. M., Obradors, C., Martinez, R. M. & Shenvi, R. A. Mn-, Fe-,
and Co-catalyzed radical hydrofunctionalizations of olefns. Chem. Rev. 116,
8912–9000 (2016).
NAtuRE CHEMiStRy | www.nature.com/naturechemistry

NaTUrE CHEmisTry
Articles
32. Isayama, S. & Mukaiyama, T. Hydration of olefns with molecular oxygen and
triethylsilane catalyzed by bis-(trifuoroacetylacetonato)cobalt(ii). Chem. Lett.
18, 569–572 (1989).
46. Shigehisa, H., Kikuchi, H. & Hiroya, K. Markovnikov-selective addition
of fuorous solvents to unactivated olefns using a Co catalyst. Chem. Pharm.
Bull. 64, 371–374 (2016).
33. Waser, J., Nambu, H. & Carreira, E. M. Cobalt-catalyzed hydroazidation
of olefns: convenient access to alkyl azides. J. Am. Chem. Soc. 127,
8294–8295 (2005).
47. Eichhorn, E., Rieker, A. & Speiser, B. Te electrochemical oxidation of
[Coii(salen)] in solvent mixtures—an example of a ladder scheme with
coupled electron-transfer and solvent-exchange reactions. Angew. Chem. Int.
Ed. 31, 1215–1217 (1992).
34. Renata, H., Zhou, Q. & Baran, P. S. Strategic redox relay enables a scalable
synthesis of ouabagenin, a bioactive cardenolide. Science 339, 56–63 (2013).
35. Shigehisa, H. et al. Catalytic hydroamination of unactivated olefns using a
Co catalyst for complex molecule synthesis. J. Am. Chem. Soc. 136,
13534–13537 (2014).
48. Merchant, R. R. et al. Divergent synthesis of pyrone diterpenes via radical
cross coupling. J. Am. Chem. Soc. 140, 7462–7465 (2018).
49. Desimoni, G., Faita, G. & Jørgensen, K. A. Update 1 of: C2-symmetric
chiral bis(oxazoline) ligands in asymmetric catalysis. Chem. Rev. 111,
PR284–PR437 (2011).
36. Li, G., Han, A., Pulling, M. E., Estes, D. P. & Norton, J. R. Evidence for
formation of a Co–H bond from (H2O)2Co(dmgBF2)2 under H2: application
to radical cyclizations. J. Am. Chem. Soc. 134, 14662–14665 (2012).
37. Crossley, S. W. M., Barabé, F. & Shenvi, R. A. Simple, chemoselective,
catalytic olefn isomerization. J. Am. Chem. Soc. 136, 16788–16791 (2014).
38. King, S. M., Ma, X. & Herzon, S. B. A method for the selective hydrogenation
of alkenyl halides to alkyl halides. J. Am. Chem. Soc. 136, 6884–6887 (2014).
39. Zhang, W. et al. Enantioselective cyanation of benzylic C–H bonds via
copper-catalyzed radical relay. Science 353, 1014–1018 (2016).
40. Wang, F., Chen, P. & Liu, G. Copper-catalyzed radical relay for asymmetric
radical transformations. Acc. Chem. Res. 51, 2036–2046 (2018).
41. Gao, D.-W. et al. Direct access to versatile electrophiles via catalytic oxidative
cyanation of alkenes. J. Am. Chem. Soc. 140, 8069–8073 (2018).
42. Green, S. A., Matos, J. L. M., Yagi, A. & Shenvi, R. A. Branch-selective
hydroarylation: iodoarene–olefn cross-coupling. J. Am. Chem. Soc. 138,
12779–12782 (2016).
43. Discolo, C. A., Touney, E. E. & Pronin, S. V. Catalytic asymmetric
radical–polar crossover hydroalkoxylation. J. Am. Chem. Soc. 141,
17527–17532 (2019).
44. Zhang, G., Fu, L., Chen, P., Zou, J. & Liu, G. Proton-coupled electron transfer
enables tandem radical relay for asymmetric copper-catalyzed
phosphinoylcyanation of styrenes. Org. Lett. 21, 5015–5020 (2019).
45. Fu, N. et al. New bisoxazoline ligands enable enantioselective
electrocatalytic cyanofunctionalization of vinylarenes. J. Am. Chem. Soc. 141,
14480–14485 (2019).
50. Zhu, R. & Buchwald, S. L. Versatile enantioselective synthesis of
functionalized lactones via copper-catalyzed radical oxyfunctionalization of
alkenes. J. Am. Chem. Soc. 137, 8069–8077 (2015).
51. Zhang, Z., Stateman, L. M. & Nagib, D. A. δ C–H (hetero)arylation via
Cu-catalyzed radical relay. Chem. Sci. 10, 1207–1211 (2019).
52. Perrotta, D., Wang, M.-M. & Waser, J. Lewis acid catalyzed enantioselective
desymmetrization of donor–acceptor meso-diaminocyclopropanes.
Angew. Chem. Int. Ed. 57, 5120–5123 (2018).
53. Redden, A. & Moeller, K. D. Anodic coupling reactions: exploring the generality
of Curtin–Hammett controlled reactions. Org. Lett. 13, 1678–1681 (2011).
54. Li, J. et al. Site-specifc allylic C–H bond functionalization with a
copper-bound N-centred radical. Nature 574, 521–561 (2019).
55. He, G., Zhao, Y., Zhang, S., Lu, C. & Chen, G. Highly efcient syntheses of
azetidines, pyrrolidines, and indolines via palladium catalyzed intramolecular
amination of C(sp3)–H and C(sp2)–H bonds at γ and δ positions. J. Am.
Chem. Soc. 134, 3–6 (2012).
56. Wayner, D. D. M., McPhee, D. J. & Griller, D. Oxidation and reduction
potentials of transient free radicals. J. Am. Chem. Soc. 110, 132–137 (1988).
57. Bloom, J. W. G., Raju, R. K. & Wheeler, S. E. Physical nature of substituent
efects in XH/π interactions. J. Chem. Teory Comput. 8, 3167–3174 (2012).
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solution via syringe. Electrolysis was initiated at a constant current of 7.0mA at
0°C. Reaction was stopped after 4.0Fmol–1 charge was passed (30h 38min). The
mixture was then diluted with ethyl acetate (200ml) and then washed with water
and brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure.
The residue was subjected to flash column chromatography on silica gel (eluted
with hexanes and ethyl acetate) to yield 299.9mg of the desired product
(71% yield) with 90% e.e. See Extended Data Fig. 1c.
Methods
General procedure for the electrochemical hydrocyanation of alkenes using a
custom-made cell (0.20mmol scale). In a 2dram vial, ligand 4 (7.6mg, 0.02mmol,
10mol%) and Cu(OTf)2 (3.6mg, 0.01mmol, 5mol%) were dissolved in DMF
(1.0ml) under a N2 atmosphere, and the mixture was stirred for 2h before use
(Solution A).58 An oven-dried, 10ml two-neck glass tube was equipped with a
magnetic stir bar, a rubber septum, a threaded Tefon cap ftted with electrical
feedthroughs, a carbon felt anode (1×0.5×0.6cm3; connected to the electrical
feedthrough via a graphite rod that was 9cm in length and 2mm in diameter) and
a platinum plate cathode (1.0×0.5cm2). To this reaction vessel, TBABF4 (132mg)
was added. Te cell was sealed and fushed with nitrogen gas for 5min, followed
by the sequential addition via syringe of the olefn substrate (0.2mmol, 1.0equiv.,
dissolved in 1ml DMF) and HOAc (60μl, 1mmol, 5 equiv.), Co(salen) 3 (0.6mg,
0.001mmol, 0.5mol%, dissolved in 1ml DMF) and Solution A. A nitrogen-flled
balloon was adapted through the septum to sustain a nitrogen atmosphere. Te
reaction vessel was then cooled to 0°C. PhSiH3 (24mg, 0.22mmol, 1.1equiv.)
and TMSCN (50μl, 0.4mmol, 2equiv.) were dissolved in DMF (1.0ml), and
the resulting solution was added to the glass tube via syringe. Electrolysis was
initiated at a cell potential of 2.3V at 0°C. Upon full consumption of the olefn
starting material as determined by thin-layer chromatography analysis, the
electrical input was removed. Te mixture was diluted with ethyl acetate (60ml)
and then washed with water (40ml) and brine, dried over anhydrous Na2SO4 and
concentrated under reduced pressure. Te residue was subjected to fash column
chromatography on silica gel (eluted with hexanes and ethyl acetate) to yield the
desired product. See Extended Data Fig. 1a.
Scale-up electrolysis using a commercial three-necked flask (5.0 mmol,
0.8 g scale). In a dried sealed tube, sBOX(tBu) 4 (190.0 mg, 0.5 mmol) and
Cu(OTf)2 (90.4 mg, 0.25 mmol) were dissolved in DMF (10.0 ml) under a N2
atmosphere, and the mixture was stirred for 2 h before use. To an oven-dried
three-neck round-bottom flask (100 ml) equipped with a magnetic stir bar
were added TBABF4 (1.98 g, 6 mmol) and olefin substrate (800 mg, 5 mmol).
Each neck was fitted with a rubber septum. The septa on the side necks were
fitted with a carbon felt anode (1.8 × 1.8 × 0.6 cm3; connected to a graphite rod
that was 9 cm in length and 2 mm in diameter) and a platinum foil cathode
(2.0 × 3.0 cm2), with the lower (closest) ends of the electrodes 1.0 cm apart.
The cell was sealed and flushed with nitrogen gas for 5 min, followed by the
addition via syringe of DMF (35 ml), HOAc (1.5 ml), Co(salen) 3 (0.025 mmol,
0.5 mol%, 15 mg dissolved in 10 ml DMF) and copper catalyst solution made in
advance. A nitrogen-filled balloon was adapted through the septum to sustain
a nitrogen atmosphere. The reaction vessel was then cooled to 0 °C. After that,
TMSCN (10 mmol, 2 equiv., 1,250 μl) and PhSiH3 (5.5 mmol, 1.1 equiv., 594 mg)
were dissolved in DMF (5.0 ml) and added to the reaction solution via syringe.
Electrolysis was initiated at a constant current of 10.0 mA at 0 °C. Reaction was
stopped after 4.0 F mol–1 charge was passed (53 h 37 min). The mixture was then
diluted with ethyl acetate (300 ml) and then washed with water and brine, dried
over anhydrous Na2SO4 and concentrated under reduced pressure. The residue
was subjected to flash column chromatography on silica gel (eluted with hexanes
and ethyl acetate) to yield 514.2 mg of desired product (55% yield) with 85% e.e.
See Extended Data Fig. 1d.
General procedure for the electrochemical hydrocyanation of alkenes using
ElectraSyn 2.0 (0.30mmol scale). The graphite plate was removed from the
ElectraSyn graphite electrode assembly to obtain the empty electrode holder and
then a piece of carbon felt (5.3×0.8×0.6cm3) was cut and fixed on the commercial
graphite electrode using Pt wire as the working electrode. Pt foil was used as the
counter electrode. In a dried sealed tube, sBOX(iPr) 60 (11.4mg, 0.03mmol)
and Cu(OTf)2 (5.4mg, 0.015mmol) were dissolved in DMF (1.0ml) under a N2
atmosphere, and the mixture was stirred for 2h before use. The ElectraSyn vial
(10ml volume) was charged with a Teflon-coated magnetic stir bar, TBABF4
(198mg, 0.6mmol) and olefin (48.0mg, 0.30mmol). The screw thread area of
the vial was covered with a rubber septum to ensure that the seal was airtight.
The carbon felt and Pt foil electrodes were adapted onto the ElectraSyn vial
cap, the vial cap was screwed onto the vial to finger tightness and the vial was
flushed with nitrogen gas for 5min. Using a syringe, DMF (3.0ml), HOAc (90mg,
1.5mmol), Co(salen) 3 (0.0015mmol, 0.5mol%, 0.9mg dissolved in 1ml DMF)
and the copper catalyst solution (prepared as in the 0.20mmol scale procedure)
were added through the rubber septum. A nitrogen-filled balloon was adapted
through the septum to sustain a nitrogen atmosphere. The electrochemical cell
was adapted onto the vial holder of the ElectraSyn 2.0, and the reaction vessel was
then cooled to 0°C using an ice bath. After that, TMSCN (0.6mmol, 75μl) and
PhSiH3 (0.33mmol, 35.7mg) were dissolved in DMF (1.0ml), which was added
to the reaction solution via syringe. The settings ‘new experiments’ at ‘constant
current’ were selected, and the current was adjusted to 3.0mA. The settings ‘No’
for ‘use of reference electrode’ were selected, and the reaction time was adjusted
to ‘10h 43min 35sec’. The setting ‘mmols substrate’ was adjusted to ‘0.3mmol’
and the polarity was chosen not to alternate. After reviewing the parameters, the
ice bath was removed and the experiment started. After electrolysis, the reaction
vial was disconnected from the ElectraSyn 2.0, the cap with electrodes was gently
removed from the vial and the reaction media was transferred to a separatory
funnel. Both electrodes were washed with ethyl acetate (20ml) to transfer any
residual product. Then, 30ml ethyl acetate was added to the separatory funnel, and
the organic solution was washed with water and brine. The organic layer was dried
with anhydrous Na2SO4 and concentrated under reduced pressure. The residue
was subjected to flash column chromatography on silica gel (eluted with hexanes
and ethyl acetate) to yield 32.0mg of the desired product (57% yield, 73% based on
recovered starting material, unoptimized) with 86% e.e. See Extended Data Fig. 1b.
General procedure for control experiments using chemical oxidants instead
electrochemistry. In a 2dram vial, sBOX(iPr) (3.5mg, 0.01mmol, 10mol%) and
Cu(OTf)2 (1.8mg, 0.005mmol, 5mol%) were dissolved in DMF (1.0ml) under a N2
atmosphere, and the mixture was stirred for 2h before use. To a dried 2dram vial,
tert-butylstyrene (16.0mg, 0.1mmol, 1.0equiv.), the oxidant (0.1mmol, 1.0equiv.)
and HOAc (30.0mg, 0.5mmol, 5.0equiv.) were added under a N2 atmosphere.
After that, Co(salen) (0.0005mmol, 0.5mol%, 0.3mg dissolved in 0.5ml DMF)
and the copper catalyst solution made in advance were added. A nitrogen-filled
balloon was adapted through the septum to sustain a nitrogen atmosphere. The
reaction vessel was then cooled to 0°C. PhSiH3 (0.11mmol, 1.1equiv., 12mg) and
TMSCN (0.2mmol, 2equiv., 25μl) were dissolved in DMF (0.5ml) and added to
the reaction solution via syringe. After stirring at room temperature for 24h, the
mixture was diluted with ethyl acetate (20ml) and then washed with water and
brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure.
Yields were determined with 1H NMR analysis using 1,3,5-trimethoxybenzene as
the internal standard. The e.e. value of the product was measured by HPLC analysis
on a chiral stationary phase.
Product derivatization: nitrile methanolysis. In a dried sealed tube, (R)-2-
(6-methoxynaphthalen-2-yl)propanenitrile 15 (21.1 mg, 0.10 mmol, 90% e.e.) and
37% HCl (1.0 ml) were dissolved in MeOH (1.0ml) under a N2 atmosphere. The
mixture was then heated at 80 °C for 48 h. After cooling to room temperature,
the mixture was extracted with ethyl acetate (30 ml) three times. The combined
organic layers were dried over anhydrous Na2SO4 and concentrated under
vacuum. Column chromatography using silica gel was then applied to yield
the desired product in 62% yield (15.1 mg) in 90% e.e. as a colourless oil. See
Extended Data Fig. 2a.
Product derivatization: indoline formation. For step 1, a solution of (R)-2-
(6-methoxynaphthalen-2-yl)propanenitrile 15 (0.3mmol, 63.3mg, 90%e.e.) and
CoCl2 (0.6mmol, 2.0equiv., 78mg) in dry methanol (3.0ml) was cooled to 0°C
under a nitrogen atmosphere. NaBH4 (3.0mmol, 10equiv., 114mg) was added
in portions. The resulting reaction mixture was then allowed to warm to room
temperature and continued to be stirred for 2h. After that, the reaction mixture
was poured into 100ml of 2M HCl at 0°C and stirred until the black precipitate
was dissolved. The mixture was washed with ethyl acetate (50ml) three times,
and the aqueous layer was made alkaline with NaOH at 0°C and then extracted
with ethyl acetate (100ml) twice. The organic layer was separated and dried over
Na2SO4, filtered and concentrated in vacuo. The crude product with 84% yield was
used directly for the next step.
For step 2, under a N2 atmosphere, a solution of S1 (43.0mg, 0.2mmol),
picolinic acid (29.5mg, 1.2equiv., 0.24mmol), EDC (57.5mg, 1.5equiv., 0.3mmol)
and DMAP (2.5mg, 0.1equiv., 0.02mmol) in dry dichloromethane (2.0ml)
was stirred at room temperature overnight. After that, the reaction mixture was
purified directly by flash column chromatography to give the desired product with
80% isolated yield. See Extended Data Fig. 2b.
Scale-up electrolysis using a commercial three-necked flask (2.0mmol, 0.4g
scale). In a dried sealed tube, sBOX(tBu) 4 (76.0mg, 0.2mmol) and Cu(OTf)2
(36.1mg, 0.1mmol) were dissolved in DMF (4.0ml) under a N2 atmosphere,
and the mixture was stirred for 2h before use. To an oven-dried three-neck
round-bottom flask (50ml) equipped with a magnetic stir bar were added TBABF4
(988mg, 3mmol) and olefin substrate (368.4mg, 2mmol). Each neck was fitted
with a rubber septum. The septa on the side necks were fitted with a carbon felt
anode (1.5×1.0×0.6cm3; connected to a graphite rod that was 9cm in length
and 2mm in diameter) and a platinum foil cathode (2.5×1.5cm2), with the lower
(closest) ends of the electrodes 0.5cm apart. The cell was sealed and flushed with
nitrogen gas for 5min, followed by the addition via syringe of DMF (24ml), HOAc
(0.6ml), Co(salen) 3 (0.01mmol, 0.5mol%, 6.0mg dissolved in 1ml DMF) and
copper catalyst solution made in advance. A nitrogen-filled balloon was adapted
through the septum to sustain a nitrogen atmosphere. The reaction vessel was then
cooled to 0°C. After that, TMSCN (4mmol, 2equiv., 500μl) and PhSiH3 (2.2mmol,
1.1equiv., 238mg) were dissolved in DMF (1.0ml) and added to the reaction
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For step 3, under a N2 atmosphere, a mixture of S2 (0.1mmol, 1.0equiv.,
32mg), Pd(OAc)2 (0.005mmol, 0.05equiv., 1.2mg), PhI(OAc)2 (0.25mmol,
2.5equiv., 80.5mg) and toluene (1ml) in a sealed tube was heated at 60°C for
24h. The reaction mixture was cooled to room temperature and concentrated
under reduced pressure. The resulting residue was purified by silica gel flash
chromatography to give the cyclized product with 92% isolated yield in 90% e.e.
60. Grimme, S. Semiempirical GGA-type density functional constructed with a
long-range dispersion correction. J. Comput. Chem. 27, 1787–1799 (2006).
61. Shao, Y. et al. Advances in molecular quantum chemistry contained in the
Q-Chem 4 program package. Mol. Phys. 113, 184–215 (2015).
62. Mardirossian, N. & Head-Gordon, M. ωB97X-V: A 10-parameter,
range-separated hybrid, generalized gradient approximation density
functional with nonlocal correlation, designed by a survival-of-the-fttest
strategy. Phys. Chem. Chem. Phys. 16, 9904–9924 (2014).
Product derivatization: dihydroisoquinolinone formation. Under a N2
atmosphere, a solution of methyl (R)-2-(1-cyanoethyl)benzoate 18 (0.1mmol,
18.9mg, 85%e.e.) and CoCl2 (0.2mmol, 2.0equiv., 26mg) in dry methanol (1.0ml)
was cooled to 0°C. NaBH4 (1.0mmol, 10equiv., 38mg) was added in portions. The
resulting reaction mixture was then allowed to warm to room temperature and
continued to be stirred for 2h. After that, the reaction mixture was heated to reflux
overnight. The resulting reaction mixture was extracted by ethyl acetate (20ml)
three times, and the combined organic layers were dried over anhydrous Na2SO4.
Purification by silica gel flash chromatography gave the cyclized product with 81%
isolated yield in 87% e.e. See Extended Data Fig. 2c.
63. Rappoport, D. & Furche, F. Property-optimized Gaussian basis sets for
molecular response calculations. J. Chem. Phys. 133, 134105 (2010).
64. Dunning, T. H. Gaussian basis sets for use in correlated molecular
calculations. I. Te atoms boron through neon and hydrogen. J. Chem. Phys.
90, 1007–1023 (1989).
65. Parrish, R. M. et al. Psi4 1.1: An open-source electronic structure program
emphasizing automation, advanced libraries, and interoperability. J. Chem.
Teory Comput. 13, 3185–3197 (2017).
66. Behn, A., Zimmerman, P. M., Bell, A. T. & Head-Gordon, M. Efcient
exploration of reaction paths via a freezing string method. J. Chem. Phys. 135,
224108 (2011).
Computational details. All geometries were optimized using the ωB97X-D59,60
density functional approximation with the 6-31G* basis set in the Q-Chem
software package61, with single-point electronic energy corrections obtained at the
ωB97X-V level of theory62 with the def2-TZVPPD basis set63 on the Cu atom and
aug-cc-pVTZ64 on all other atoms in the Psi4 software package65. Rotations about
the carbon–ester bond (C1–C2 in Fig. 5) and the Cu–substrate bond, as well as
various different axial/equatorial Cu-ligand coordination geometries, were sampled
as starting points for geometry optimizations during the searches for the global
energy minima of the catalytic intermediates. The frozen string algorithm66,67
was also used as an aid during transition state searches. Analytical vibrational
frequencies confirmed the nature of all stationary points, wherein transition state
structures each contained a single imaginary frequency connecting the catalytic
intermediate structure and the corresponding product. Thermal contributions to
the free energy were computed at 273.15K using partition functions derived within
the ideal gas, rigid rotor, and harmonic oscillator approximations. See Extended
Data Fig. 2.
67. Sharada, S. M., Zimmerman, P. M., Bell, A. T. & Head-Gordon, M.
Automated transition state searches without evaluating the Hessian.
J. Chem. Teory Comput. 8, 5166–5174 (2012).
Acknowledgements
Financial support to S.L. was provided by NIGMS (R01GM130928) and Eli Lilly.
Financial support to B.G.E. and R.A.D. was provided by start-up funding from Cornell
University. This study made use of the NMR facility supported by the NSF (CHE-
1531632) and resources of the National Energy Research Scientific Computing Center
(NERSC), a US Department of Energy Office of Science User Facility operated under
contract no. DE-AC02-05CH11231. We thank K. Moeller for helpful discussions, A.
Condo for gas chromatography mass spectrometry analysis, Y. Shen and J. Liu for
providing some of the substrates and IKA for donation of the ElectraSyn 2.0.
Author contributions
S.L. conceived of the project. L.S., N.F., M.O.F. and S.L. designed the experiments. L.S.,
N.F. and W.H.L. carried out the experiments. B.G.E. and R.A.D. designed and carried
out all DFT calculations. B.G.E., R.A.D and S.L. analysed the DFT data. All authors
contributed to writing the manuscript.
Data availability
The data that support the findings of this study are included in this published
article and its Supplementary Information files. Crystallographic data for
compound 4 has been deposited at the Cambridge Crystallographic Data Centre
under deposition number 1978310 and can be obtained free of charge (http://www.
ccdc.cam.ac.uk/data_request/cif).
Competing interests
The authors declare no competing interests.
Additional information
References
Extended data is available for this paper at https://doi.org/10.1038/s41557-020-0469-5.
58. Fu, N., Sauer, G. S. & Lin, S. A general, electrocatalytic approach to the
synthesis of vicinal diamines. Nat. Protoc. 13, 1725–1743 (2018).
59. Chai, J.-D. & Head-Gordon, M. Long-range corrected hybrid density
functionals with damped atom–atom dispersion corrections. Phys. Chem.
Chem. Phys. 10, 6615–6620 (2008).
Supplementary information is available for this paper at https://doi.org/10.1038/
s41557-020-0469-5.
Correspondence and requests for materials should be addressed to R.A.D. or S.L.
Reprints and permissions information is available at www.nature.com/reprints.
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Extended Data Fig. 1 | Methods for electrochemical hydrocyanation of alkenes. a, Electrochemical hydrocyanation of alkenes using a custom-made cell58
(0.20ꢀmmol scale). b, Electrochemical hydrocyanation of alkenes using ElectraSyn 2.0 (0.30ꢀmmol scale). c, Electrolysis using a commercial three-necked
flask (2.0ꢀmmol scale). d, Electrolysis using a commercial three-necked flask (5.0ꢀmmol scale). Detailed experimental procedures can be found in the
Methods section.
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Extended Data Fig. 2 | Methods for product derivatization. a, Derivatization of product 15 to naproxen methyl ester 56 (analogue of naproxen).
b, Derivatization of product 15 to benzoindoline 57 (analogue of duocarmycin). c, Derivatization of product 18 to dihydroisoquinolone 58 (analogue of
palonosetron). Detailed experimental procedures can be found in Methods section.
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