Enantioselective cyanation of benzylic C-H bonds via copper-catalyzed radical relay

Article abstract of DOI:10.1126/science.aaf7783

Direct methods for stereoselective functionalization of sp-hybridized carbon-hydrogen [C(sp³)-H] bonds in complex organic molecules could facilitate much more efficient preparation of therapeutics and agrochemicals. Here, we report a copper-catalyzed radical relay pathway for enantioselective conversion of benzylic C-H bonds into benzylic nitriles. Hydrogen-atom abstraction affords an achiral benzylic radical that undergoes asymmetric C(sp³)-CN bond formation upon reaction with a chiral copper catalyst. The reactions proceed efficiently at room temperature with the benzylic substrate as limiting reagent, exhibit broad substrate scope with high enantioselectivity (typically 90 to 99% enantiomeric excess), and afford products that are key precursors to important bioactive molecules. Mechanistic studies provide evidence for diffusible organic radicals and highlight the difference between these reactions and C-H oxidations mediated by enzymes and other catalysts that operate via radical rebound pathways.

Full text of DOI:10.1126/science.aaf7783

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Evidence of Sr leaching and minor surface re-
arrangement of the resulting IrOx films suggests
that an IrOx/SrIrO3 catalyst is formed in situ and
becomes increasingly active over the first 2 hours
of electrochemical testing. Although the exact
structure of the surface formed during reaction
is still unknown, DFT calculations have identified
possible structures that could be kinetically or
epitaxially stabilized by the interface with SrIrO3
and could contribute to the very high observed
activity. The stability and high intrinsic activity
of this catalyst show promise for its integration
into renewable energy technologies, such as
polymer electrolyte membrane electrolyzers, for
the sustainable production of hydrogen or other
fuels and chemicals.
ORGANIC CHEMISTRY
Enantioselective cyanation
of benzylic C–H bonds via
copper-catalyzed radical relay
Wen Zhang,1* Fei Wang,1* Scott D. McCann,2 Dinghai Wang,1 Pinhong Chen,1
Shannon S. Stahl,2† Guosheng Liu1†
Direct methods for stereoselective functionalization of sp3-hybridized carbon–hydrogen
[C(sp3)–H] bonds in complex organic molecules could facilitate much more efficient
preparation of therapeutics and agrochemicals. Here, we report a copper-catalyzed radical
relay pathway for enantioselective conversion of benzylic C–H bonds into benzylic
nitriles. Hydrogen-atom abstraction affords an achiral benzylic radical that undergoes
asymmetric C(sp3)–CN bond formation upon reaction with a chiral copper catalyst.
The reactions proceed efficiently at room temperature with the benzylic substrate
as limiting reagent, exhibit broad substrate scope with high enantioselectivity (typically
90 to 99% enantiomeric excess), and afford products that are key precursors to
important bioactive molecules. Mechanistic studies provide evidence for diffusible
organic radicals and highlight the difference between these reactions and C–H
oxidations mediated by enzymes and other catalysts that operate via radical
rebound pathways.
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the number of stereogenic centers in the
molecule (1). Consequently, synthetic meth-
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reaction of an achiral carbon radical with a chiral
copper(II) species (L*CuII–CN) (13), a pathway that
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alization reactions that involve selective, stereo-
specific activation of a prochiral C–H bond within
an organic molecule (14, 15).
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Cu-catalyzed methods for oxidation of styrenes
and other alkenes [for example, (16, 17)], as well
as C–H bonds (18). The former reactions are
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radical intermediate with copper(II), generating
an organocopper(III) species that undergoes
reductive elimination to afford a new C–C or
C–heteroatom bond. This pathway, which resem-
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with a transition-metal center [e.g., (13, 19–23)],
prompted us to consider how analogous con-
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Sosnovsky allylic oxidations and related reac-
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(24, 25); however, these reactions face constraints
that have greatly limited their synthetic utility
over the nearly 60-year history of the reaction. For
example, the alkene substrate is almost always
used in large excess relative to the peroxide-
based oxidant, a feature that severely restricts
the net product yield and, in turn, the scope of
suitable substrates. The majority of examples
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T
ods that enable stereoselective functionalization
of C(sp3)–H bonds could have a major effect on
the discovery and development of new pharma-
ceuticals. Enzymatic oxygenases and halogenases,
such as cytochrome P450 and nonheme iron en-
zymes (2–4), have inspired the discovery of synthet-
ic methods for selective oxidation of C–H bonds
[see, for example, (5–8)]. These enzymes and related
small-molecule catalysts function via generation
of a reactive metal-oxo species that abstracts
an H atom from a C(sp3)–H bond, followed by
radical rebound (9) to the metal-bound hydroxide
or halide group (Fig. 1A). Here, we report a com-
plementary radical relay strategy for C(sp3)–H oxi-
dation whereby a reactive radical (X·) abstracts
a hydrogen atom from an sp3-hybridized carbon
atom to produce a diffusible organic radical. This
radical is then trapped by a second species that
generates the functionalized sp3 center (Fig. 1B).
This concept is demonstrated in copper-catalyzed
enantioselective cyanation of benzylic C–H bonds
(Fig. 1C). Optically pure alkyl nitriles are featured
in many bioactive natural products, pharmaceuti-
cals, and agricultural chemicals (10). Moreover,
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ACKNOWLEDGMENTS
This work was supported by the U.S. Department of Energy (DOE),
Office of Science, Office of Basic Energy Sciences, under contract
no. DE-SC0008685 and through the SUNCAT Center for Interface
Science and Catalysis. Partial support was provided by the Center
on Nanostructuring for Efficient Energy Conversion at Stanford
University, an Energy Frontier Research Center funded by the DOE,
Office of Science, under award no. DE-SC0001060. L.C.S. received
fellowship support from the DARE (Diversifying Academia, Recruiting
Excellence) Doctoral Fellowship supported by the Vice Provost for
Graduate Education at Stanford University. Part of this work was
performed at the Stanford Nano Shared Facilities. K.N., Y.H., and H.Y.H.
acknowledge support from the DOE, Office of Science, Office of
Basic Energy Sciences, Division of Materials Sciences and Engineering,
under contract no. DE-AC02-76SF00515 (thin film synthesis), and
from the Global Climate and Energy Project at Stanford University
(modifications under ionic tuning). C.F.D. and C.K. acknowledge
support from the NSF Graduate Research Fellowship program
under grant no. DGE-114747. C.K. also acknowledges support
from the Morgridge Family Stanford Graduate Fellowship.
1State Key Laboratory of Organometallic Chemistry, Shanghai
Institute of Organic Chemistry, University of Chinese Academy
of Sciences, Chinese Academy of Sciences, 345 Lingling
Road, Shanghai 200032, China. 2Department of Chemistry,
University of Wisconsin–Madison, 1101 University Avenue,
Madison, WI 53706, USA.
*These authors contributed equally to this work. †Corresponding
author. Email: stahl@chem.wisc.edu (S.S.S.); gliu@mail.sioc.
ac.cn (G.S.L.)
SUPPLEMENTARY MATERIALS
www.sciencemag.org/content/353/6303/1011/suppl/DC1
Materials and Methods
Figs. S1 to S8
Tables S1 to S2
References (24–52)
22 February 2016; accepted 9 August 2016
10.1126/science.aaf5050
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Fig. 1. Strategies for hydrogen-atom-transfer–mediated C–H oxidation. (A) Radical rebound mechanism for enzymatic and biomimetic C–H hydroxylation
and halogenation (X = halide). (B) Radical relay pathway for C–H oxidation involving formation of a free radical that is trapped by a reactive metal center. (C) Proposed
mechanism for Cu-catalyzed enantioselective cyanation of benzylic C–H bonds via radical relay.
as cyclopentene and cyclohexene. Reports of
enantioselective reactivity retain this limited
substrate scope and are characterized by poor
catalytic efficiency that can result in multiday
reaction times (26, 27). A synthetically useful
radical-relay C–H oxidation method would need
to overcome these limitations.
(PhCO2)2, oxone, N-fluorobenzenesulfonylimide
(NFSI), and Selectfluor-BF4, were tested in the
cyanation of 1-ethylnaphthylene, 1a, with tri-
methylsilyl cyanide (TMSCN) as cyanide source
and [Cu(MeCN)4]PF6 as the copper(I) catalyst (see
the supplementary materials for screening data).
An achiral bis(oxazoline) ligand (L1) was included
in the reactions, but virtually all of the reactions
failed to give the desired cyanation product. NFSI
was the only oxidant that afforded any amount
of the benzylic nitrile (2a). The yield increased upon
changing the solvent from acetonitrile to chloro-
benzene and using CuOAc as the copper source
(L1, 25% yield) (Fig. 2). Replacing the ligand L1
with an enantiomerically pure, benzyl-substituted
bisoxazoline (BOX) derivative L2 and performing
the reaction in benzene led to a significant improve-
ment in the yield (up to 91%) and also afforded
product 2a in excellent (96%) enantiomeric excess
(ee) (Fig. 2). In each of the reactions in Fig. 2, small
quantities (trace to 12%) of benzylimide product
derived from coupling with the bis(sulfonyl)imide
of NFSI (30) were detected by proton nuclear
magnetic resonance (1H NMR) spectroscopy.
Assessment of various ligands showed that
BOX ligands were the most effective ligand class,
and testing of other BOX-ligand variants led
to further insights and improvements (Fig. 2).
Replacement of the gem-dimethyl substituents
with a spirocyclic cyclopentyl group (L3) improved
the enantioselectivity to 95% ee, whereas use of
tert-butyl substituents on the oxazolines (L4),
rather than benzyl groups, led to a significant
dropoff in yield and enantioselectivity. Only trace
product was observed with a ligand having an un-
substituted methylene linker between the two
oxazolines (L5). Some of the best enantioselec-
tivities were obtained with indane-derived BOX
ligands, in particular, L6 and L8.
In an effort to explore the scope of the benzylic
cyanation reaction, three conditions identified in
Fig. 2 were tested with a wide range of alkylarene
substrates (Fig. 3). Simple 1-alkyl–substituted
naphthylenes proved to be good substrates, provid-
ing the desired products 2a to 2c with excellent
enantioselectivities (96 to 97% ee) in yields of 72 to
91%. Product 2d, with a free primary alcohol, was
obtained in excellent enantioselectivity (95% ee),
but the reaction proceeded with only moderate
conversion, resulting in a 42% product yield with
52% unreacted starting material. The analogous
homobenzylic acetate derivative, however, exhibited
very good reactivity (87% yield of 2e), while re-
taining excellent enantioselectivity (99% ee). Ver-
satile functional groups appended to the aliphatic
chain, such as chloride, azide, phthalimide (Nphth),
and carboxylic ester, were very well tolerated (2f
to 2j). A trifluoromethane sulfonate (OTf) group
on the aromatic ring did not interfere with the
reaction (products 2k and 2m) and provides a
basis for subsequent derivatization of the product
into more-complex molecules. The compatibility
of these potentially sensitive functional groups
included a primary alkyl bromide precursor to a
CCR1 receptor antagonist of interest for treatment
The pharmaceutical interest in benzylic ni-
triles and products derived therefrom, together
with the formation of benzylic nitriles in certain
alkene difunctionalization reactions (17, 28) [for
broader context, see (29)], prompted us to target
a method for enanatioselective cyanation of benzylic
C–H bonds. Initial efforts focused on generation of
benzylic radicals via hydrogen-atom abstraction in
the presence of copper(II) and a cyanide source.
We posited that reductive activation of peroxides
and other diheteroatom-bonded oxidants (see
X–Z, Fig. 1C) with a copper(I) source should afford
a reactive radical species and copper(II). A series of
oxidants, including tBuO2H, (tBuO)2, PhCO3 Bu,
t
Fig. 2. Reaction opti-
mization and represent-
ative ligand screening
data. General reaction
conditions: 1a (0.2 mmol),
trimethylsilyl cyanide
(TMSCN) (0.6 mmol),
NFSI (0.3 mmol), CuOAc
(0.02 mmol), and lig-
and (0.024 mmol) in
1.0 mL of solvent at r.t.
for 10 hours. Yield de-
termined by 1H NMR,
CF3CONMe2 as internal
standard. The ee value
was determined by high-
performance liquid chro-
matography (HPLC) with
a chiral stationary phase.
*Reaction conducted in
chlorobenzene.
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Fig. 3. Substrate scope and synthetic applications of Cu-catalyzed cyanation of benzylic C–H bonds. (A) Substrate scope. (B) Synthetic applications.
*Reaction conditions: alkylarene as the limiting reagent (0.2 to 1 mmol scale), 10 mole % (mol %) CuI(OAc), 12 mol % ligand; 1.5 equivalent (equiv) NFSI, 3 equiv
TMSCN, C6H6 (0.2 M substrate); under N2; isolated yields reported. Absolute stereochemical assignments are based on x-ray crystallographic characterization of (R)-
and (S)-2h; see section 5 in the supplementary materials for details. Negative ee values reflect the opposite enantiomeric configuration relative to that depicted
graphically. †Chlorobenzene used as the solvent. ‡ee value of product after recrystallization. §See (34).
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Good results were observed in the reaction of
4-isobutyl biphenyl (2z), demonstrating toler-
ance of branching in the homobenzylic position
(see below for further discussion). Tertiary ben-
zylic C–H bonds and substrates with larger sub-
stituents in the homobenzylic position were
found to be unreactive with these catalyst sys-
tems, presumably because they present too much
steric hindrance for effective hydrogen-atom ab-
straction. Numerous substrates containing phar-
maceutically relevant heterocycles were tested,
including those with a pyrazole, carbazole, benzo-
thiazole, benzoxazole, thiophene, and pyridine
(3c to 3i). Yields ranged from moderate to ex-
cellent (up to 89%), whereas enantioselectivities
were consistently good to excellent (up to 98% ee).
Alkyl phenol and anilide substrates were found
to be unreactive. In these cases, the presence
of weak O–H and N–H bonds could serve as
radical traps. Benzene was typically used as the
solvent in these reactions, on the basis of the
initial optimization results, but a number of sub-
strates were also tested in chlorobenzene as an
alternate less toxic solvent, and excellent results
were obtained (see 2a, 2c, 2e, 2f, 2h, 2p, 2r, 2v,
3c, and 3h). In addition, four substrates were
demonstrated on a 1- to 5-g scale to establish prac-
tical laboratory-scale utility (2c, 2h, 3d, and 3h).
The results in Fig. 3 represent the most stream-
lined method to date for the preparation of
enantiomerically enriched benzylic nitriles from
readily available starting materials. Asymmetric
hydrocyanation of vinylarenes is perhaps the most
compelling alternative. Such methods have been
known for some time (32) and are the subject of
ongoing development (33), but the present meth-
ods exhibit advantages with respect to substrate
accessibility (i.e., access to alkyl- versus vinyl-
substituted arenes), functional-group compatibil-
ity and substrate scope, and enantioselectivity
relative to asymmetric hydrocyanation of alkenes.
The enantiomerically enriched nitriles derived
from these reactions are excellent precursors to
phenethylamine and arylacetic acid derivatives.
For example, benzylic nitriles 2d and 2h were
subjected to hydrogenation over a Raney nickel
catalyst, and the resulting primary amines were
converted to a Boc (tert-butyloxycarbonyl) deriv-
ative before isolation. This sequence afforded the
desired products in good yield with no loss in ee
relative to the starting material (Fig. 3B, ii). Tra-
ditional methods for nitrile hydrolysis (e.g., in
the presence of aqueous acid) erode the enanti-
omeric excess, but a number of biocatalytic pro-
cesses are emerging for nitrile hydrolysis that
proceed under very mild conditions (34). Although
these enzymatic methods were not explored in the
present study, they provide an excellent strategy
for conversion of nitriles to arylacetic acids and
could even provide a means to upgrade the enantio-
selectivity (Fig. 3B, iii).
Fig. 4. Experimental and computational studies providing insight into the mechanism of the copper-
catalyzed cyanation reaction. These include (A) reaction selectivity studies, (B) kinetic isotope effects,
(C) radical trapping experiments, and (D) DFT computational studies.
of chronic inflammation (31), highlighting the
mildness of reaction conditions (Fig. 3B, i). 2-Alkyl
naphthylenes also proved to be good substrates
for the enantioselective cyanation, affording
products 2l and 2m in good yield and enantio-
selectivity. Desymmetrization of acenaphthene (2n)
was achieved with good enantioselectivity (79% ee).
Ethyl- and related alkylbenzene derivatives
were similarly effective for this transformation
(products 2o to 2z and 3a and 3b). The cases
with reduced yields (e.g., 40 to 60%) typically
reflect poor conversion, which would allow for
recovery of valuable unreacted starting material,
if desired. The enantioselectivity typically remained
excellent (>90%). With substrates featuring more
than one benzylic C–H site (e.g., 2n, 2r to 2t,
2y, and 3a), selectivity for the monocyanation
product was observed, with consistently high ee.
Several observations suggest that site selectiv-
ity in these reactions is influenced by both steric
and electronic effects (Fig. 4A). Subjection of
2-ethylfluorene 4b to the Cu-catalyzed cyanation
conditions results in selective cyanation of the
benzylic site of the 2-ethyl group; no cyanation
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of the highly activated, doubly benzylic meth-
ylene group of the fluorene is observed. We
attribute this outcome to steric effects. The con-
tribution of electronic effects is evident in the
reactivity of the substituted phenethylnaptha-
lene derivatives 4c to 4f. The site selectivity with
these substrates is quite high, always favoring
the benzylic position adjacent to the naphtha-
lene, but the preference increases from 12:1 to
29:1 as the substituent at the para position
changes from an electron-donating tert-butyl
group to an electron-deficient –CF3 group. Ex-
cellent enantioselectivity (97 to 98% ee) is ob-
served in each case. The site selectivity is further
evident from the reaction of the homobenzylic
methyl ether substrate 4g, which affords only
the benzylic C–H cyanation product in good
yield and excellent ee. Similarly, benzylic over
tertiary C–H activation is observed in the forma-
tion of 2z and suggests that the reactive imidyl
radical shows exquisite selectivity in the hydrogen-
atom-transfer (HAT) reaction. This observation con-
trasts with more potent HAT reagents, such as
photoexcited benzophenone, which exhibit only
modest selectivity toward different C–H bonds (35).
Stereoselectivity issues were probed in the
reaction of enantiomerically pure homobenzylic
acetate (R)-4h. Catalysts with each of the enan-
tiomers of ligand L3 were tested, and both led
to products with excellent diastereoselectivity,
reflecting high levels of catalyst- rather than
substrate-controlled stereoselectivity. The differ-
ences in diastereomeric ratio and yield of the two
products probably reflect a matched-mismatched
effect between the ligand and substrate chirality.
A competition deuterium kinetic isotope effect
(KIE) study, employing a mixture of 1a and 1a-d2,
revealed a KIE of 3.5 (Fig. 4B). On the other hand,
independent measurement of the reaction rate
of these two substrates revealed only a modest
difference in rate (KIE = 1.6 0.2). These values
suggest that C–H cleavage is only partially turnover-
limiting and that another mechanistic step also
contributes to the catalytic turnover rate (e.g.,
generation of the reactive radical via activation
of NFSI by CuI). Additional mechanistic studies
are ongoing to secure further insights, but several
observations provide clear evidence for formation
of a diffusible carbon-centered radical in the re-
action (Fig. 4C). Subjection of the cyclopropane-
containing substrate 4i to the reaction conditions
results in a mixture of the benzylic cyanation
product 5i and a ring-opened product (7) in 7%
and 32% yield, respectively, together with a mix-
ture of other unidentified by-products. Addi-
tional evidence for a radical intermediate was
obtained by performing the catalytic reactions
of 1-ethylnaphthalene (1a) in the presence of O2
or BrCCl3. Under ambient air as a source of O2,
the reaction generated the racemic benzylic alco-
hol and ketone in 24% and 55% yields, respec-
tively. This product mixture is consistent with
trapping of the organic radical by O2 and sub-
sequent conversion of the organic peroxyl radical
into the alcohol/ketone mixture. No cyanation
product (2a) was observed under the aerobic con-
ditions. When the reaction was performed in the
presence of BrCCl3 (2 equivalents), a mixture of
the benzylic nitrile and bromide products was ob-
tained (44 and 24% yields, respectively). This product
ratio, together with precedent for efficient trapping
of organic radicals by BrCCl3 (36), implicates very
rapid trapping of organic radicals by a chiral
L*CuII(CN) species under the reaction conditions.
The proposed reaction of organic radicals with
a L*CuII(CN) species is the subject of ongoing
investigation, but the high enantioselectivity
observed in the reactions suggests that the benzylic
position is in close proximity to the chiral Cu
center in the enantioselectivity-determining step.
A plausible pathway involves reaction of the in-
termediate organic radical with CuII, an open-shell,
d9 metal center, to afford a benzyl–CuIII species.
Preliminary density functional theory (DFT) calcu-
lations support the viability of this pathway (Fig.
4D). An ethylbenzene-derived radical reacts at
CuII in an (L2)CuII(CN)2 species with a low bar-
rier to afford a benzyl-CuIII species. Subsequent
C(sp3)–CN reductive elimination generates the
benzylic nitrile product. The calculations suggest
that the transition state for the addition of the
benzylic radical to CuII is lower in energy than
reductive elimination, indicating that formation
of the alkyl-CuIII species is reversible and that
enantioselectivity is determined by the reductive
elimination step. An analogous conclusion was
reached in a recent DFT study of Ni-catalyzed
cross-coupling reactions, wherein reversible addi-
tion of an alkyl radical to a NiII catalyst precedes
enantiodetermining reductive elimination (37). For
the present system, the difference in the computed
activation free energy (DDG‡) for reductive elim-
ination of the two enantiomeric benzylic nitriles
(1.6 kcal/mol) is very similar to the DDG‡ associated
with the experimentally observed enantioselec-
tivity (e.g., DDG‡ = 1.5 kcal/mol for 2q) (Fig. 3).
Moreover, the reductive elimination transition
states for this pathway are calculated to be slightly
lower than the calculated barrier for bromine
transfer from BrCCl3 to an ethylbenzene-derived
radical (DG‡ = 12.2 kcal/mol) (Fig. 4D), matching
the slight preference for cyanation over bromi-
nation noted in Fig. 4C. Although the agreement
between the computed pathways and several key
experimental observations is quantitatively closer
than can be justified by the uncertainties in the
computational methods, the qualitative agreement
is consistent with the proposed radical coupling
pathway with L*CuII(CN)2.
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ACKNOWLEDGMENTS
Financial support for this project was provided by the
National Basic Research Program of China (973-2015CB856600),
the National Natural Science Foundation of China (nos.
21225210, 21421091, 21532009, and 21472217) (G.S.L.),
a National Institutes of Health predoctoral fellowship (F31-
GM116443) (S.D.M.), and the Department of Energy
(DE-FG02-05ER15690) (S.S.S.). The NSF provided partial support
for the computational resources (CHE-0840494). G.S.L.
thanks X. L. Wan at Shanghai Institute of Organic Chemistry
for his assistance with HPLC analysis. Metrical parameters
for the structures of (R)- and (S)-2h are available free of
charge from the Cambridge Crystallographic Data Centre under
accession numbers CCDC-1496364 and -1495535, respectively.
The copper-catalyzed method for enantioselec-
tive cyanation of C(sp3)–H bonds described herein
represents a valuable demonstration of radical
relay catalysis. The ability to use the C(sp3)–H
substrate as the limiting reagent, together with
the mild reaction conditions, excellent enantio-
selectivity, and broad substrate scope, provide key
foundations for the pursuit of other chemo-, regio-,
and stereoselective C–H oxidation reactions.
SUPPLEMENTARY MATERIALS
www.sciencemag.org/content/353/6303/1014/suppl/DC1
Materials and Methods
Figs. S1 to S3
Tables S1 to S3
References (38–60)
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29 March 2016; accepted 1 August 2016
10.1126/science.aaf7783
1018 2 SEPTEMBER 2016 • VOL 353 ISSUE 6303
sciencemag.org SCIENCE

Enantioselective cyanation of benzylic C−H bonds via
copper-catalyzed radical relay
Wen Zhang, Fei Wang, Scott D. McCann, Dinghai Wang, Pinhong
Chen, Shannon S. Stahl and Guosheng Liu (September 1, 2016)
Science 353 (6303), 1014-1018. [doi: 10.1126/science.aaf7783]
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