Enantioselective Olefin Hydrocyanation without Cyanide

Article abstract of DOI:10.1021/jacs.9b10875

The enantioselective hydrocyanation of olefins represents a conceptually straightforward approach to prepare enantiomerically enriched nitriles. These, in turn, comprise or are intermediates in the synthesis of many pharmaceuticals and their synthetic derivatives. Herein, we report a cyanide-free dual Pd/CuH-catalyzed protocol for the asymmetric Markovnikov hydrocyanation of vinyl arenes and the anti-Markovnikov hydrocyanation of terminal olefins in which oxazoles function as nitrile equivalents. After an initial hydroarylation process, the oxazole substructure was deconstructed using a [4 + 2]/retro-[4 + 2] sequence to afford the enantioenriched nitrile product under mild reaction conditions.

Full text of DOI:10.1021/jacs.9b10875

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Communication
Enantioselective Olefin Hydrocyanation Without Cyanide
Alexander W. Schuppe, Gustavo M. Borrajo-Calleja, and Stephen L. Buchwald
J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 05 Nov 2019
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Enantioselective Olefin Hydrocyanation Without Cyanide
Alexander W. Schuppe,† Gustavo M. Borrajo-Calleja,† Stephen L. Buchwald*
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Department of Chemistry, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, Massachusetts
02139, United States
Supporting Information Placeholder
A. Prototypical Asymmetric Olefin Hydrocyanation
ABSTRACT: The enantioselective hydrocyanation of
▪
CN
olefins represents
a
conceptually straightforward
In situ generated or direct use of HCN
R2
R2
H-CN
R1
R1
*
Highly regioselective
approach to prepare enantiomerically enriched nitriles.
These, in turn, comprise or are intermediates in the
synthesis of many pharmaceuticals and their synthetic
derivatives. Herein, we report a cyanide-free dual
Pd/CuH-catalyzed protocol for the asymmetric
Markovnikov hydrocyanation of vinyl arenes and the
anti-Markovnikov hydrocyanation of terminal olefins in
which oxazoles function as nitrile equivalents. After an
initial hydroarylation process, the oxazole substructure
was deconstructed using a [4+2]/retro-[4+2] sequence to
afford the enantioenriched nitrile product under mild
reaction conditions.
[Ni], L*
B. This Approach: Enantioselective Hydrocyanation of Vinyl Arenes
cyanide-free
O
CN
3
R2
R2
R1
R1
formal asymmetric
N
X
olefin hydrocyanation
1
2
O
6
retro-[4+2]
Cu Pd
O
R
O
N
N
R1
R
R
[4+2]
R
R2
R2
R1
4
5
[not isolated]
Nitriles are a ubiquitous class of compounds present in many
pharmaceuticals,1 secondary metabolites,2 and polymers.3 Owing
to their unique chemical reactivity, nitriles often serve as precursors
to numerous additional important functional groups in organic
synthesis, including N-heterocycles, carbonyl compounds, and
amines.4 Although nitriles can be accessed by many methods, the
conversion of olefins to alkyl nitriles via transition metal-catalyzed
olefin hydrocyanation represents one of the most conceptually
straightforward processes. While hydrocyanation of feedstock
olefins is conducted on a million-metric ton scale annually to
produce nitrile precursors to polymers,3 these protocols employ
hydrogen cyanide and form almost exclusively achiral products.
Despite the numerous improvements in the racemic hydrocyanation
of olefin feedstocks5 and fine chemicals,6 the reaction conditions
and substrates employed in the analogous asymmetric variant of
this transformation have advanced minimally since the seminal
work by Jackson7a and RajanBabu.7b–7d,7g
C. Proposed Dual Catalytic Cycle
L*Cu
Pd
X
L
O
R2
N
R1
O
N
2
X
R2
II
R1
IV
1
L*CuH
LPd
III
Copper
Palladium
I
R3SiOR,
MX
R1
O
L Pd
N
R2
R2
L*CuX
VI
N
R1
R3SiH,
MOR
O
4
V
Figure 1. A. Traditional approaches to asymmetric olefin
hydrocyanation. B. Our dual Pd/CuH-catalyzed asymmetric olefin
hydrocyanation using oxazoles as masked nitriles, followed by a
thermal deconstruction of 4 to the enantioenriched nitrile. C.
Asymmetric olefin hydrocyanation is typically achieved through
the formal addition of hydrogen cyanide, either generated in situ or
employed directly in gaseous form, across an olefin facilitated by a
chiral phosphine-ligated metal catalyst (Scheme 1A).7–8 Aside from
the potential safety concerns of working with hydrogen cyanide,9
many of these asymmetric methods are limited to vinyl arenes and
employ non-commercially available ligands.7,10 Recently, Zhang
and Lv have described a formal asymmetric olefin hydrocyanation
Proposed
dual
Pd/CuH
catalytic
cycles
for
the
hydrofunctionalization process involving a 2-halo-oxazole (2).
C–H cyanation,12 α-arylation of prefunctionalized nitriles13 and
enantioselective protonation of silyl ketene imines,14 have also
been developed employing various precursors.15
Our continued interest in enantioselective alkene
hydrofunctionalization reactions led us to envision the
development of a catalytic protocol to access enantioenriched α-
alkyl-α-arylnitriles, represented by 3 (Figure 1B).16–18 We proposed
reaction by means of
a
tandem rhodium-catalyzed
hydroformylation/condensation/aza-Cope elimination sequence.11
Alternative methods to access enantioenriched nitriles, including
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that the critical C–CN bond of the nitrile could be forged through
Table 1. Optimization of the enantioselective hydrocyanation of
styrene (1a).a
1
2
3
4
5
6
7
8
an initial dual Pd/CuH-catalyzed asymmetric olefin
hydroarylation17 reaction using a N-heterocyclic compound as a
nitrile surrogate, thus obviating the need to employ cyanide either
directly or transiently formed. A subsequent thermal-[4+2]/retro-
[4+2] sequence with the appropriate dienophile could furnish the
enantioenriched nitrile. However, at the outset, it was unclear to us
which N-heterocycle would best serve as a masked nitrile, since
pyrimidines, pyrazines, oxazoles and several other heterocycles
have all been shown to expel nitriles as byproducts in cycloaddition
reactions with alkynes.19–21 We reasoned that an oxazole, despite
its limited precedent in forming nitriles,19 would be an ideal nitrile
precursor for this transformation as it does not introduce any
regiochemical complications and is an electron-rich aza-diene.21
i. P1 (6.0 mol%), Me2PhSiH (2.0 equiv)
NaOTMS (2.0 equiv), BrettPhos (6.0 mol%)
R
[Pd(cinnamyl)Cl]2 (6.0 mol% [Pd]),
THF [0.6], 45 ºC, 16 h
O
CN
3a
Ph
Ph
Ph
Me
N
CO2Et
(7a) (3.5 equiv)
PhMe [4.0], 110 C, 8 h
ii. EtO2C
X
1a
2a-c
(1.0 equiv)
(1.3 equiv)
variation from standard conditions
% yield
er
entry
1
2
3
4
5
6
7
8
9
10
none, 2a (X=Br, R=Me)
P2
6.0 mol% CuOAc + 7.0 mol% L1
6.0 mol% Cu(OAc)2 + 7.0 mol% L1
6.0 mol% CuOAc + 7.0 mol% L2
XPhos (L4)
96%
88%
94%
82%
81%
61%
14%
0%
97:3
80:20
97:3
72:28
99:1
87:13
nd
nd
90:10
nd
9
10
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60
t-BuBrettPhos (L5)
no Pd and BrettPhos
2b (X=Br, R=Ph)
35%
5%
2c (X=Cl, R=Me)
Figure 1C details our proposed dual Pd/CuH catalytic cycle for
the aforementioned approach. Enantioselective hydrocupration of
an olefinic substrate (1) by a CuH catalyst (I), generated in situ
through the use of a Cu(I) salt, chiral phosphine ligand, and silane,
would form an enantioenriched Cu(I) alkyl intermediate (II).
Meanwhile, the Pd catalytic cycle would begin with oxidative
addition of a ligated Pd(0) species (III) into a 2-halo-oxazole (2)
forming complex IV. Stereospecific transmetallation of II with Pd
species IV would result in an alkyl Pd(II) complex (V), which
following reductive elimination furnishes an intermediate
enantioenriched oxazole (4). The formed copper(I) halide (VI)
could regenerate the active CuH catalyst after a -bond metathesis
reaction in the presence of an appropriate base and silane.17–18 For
this approach to be successful, the rates of both catalytic cycles
would need to be well aligned to prevent any deleterious side
pathways or the racemization of the alkyl copper species II.17 After
this hydroarylation process, as depicted in Figure 1B, a subsequent
thermal-[4+2] cycloaddition between oxazole 4 and an alkyne
would form a highly strained 7-oxa-2-azabicyclo[2.2.1]heptadiene
derivative (5), and upon a retro-[4+2] cycloaddition the nitrile
product is liberated along with an electron deficient furan (6). Thus,
we reasoned that the judicious choice of a 2,5-disubstituted-4-halo-
oxazole (2) coupling partner would be paramount to achieving both
a highly enantioselective hydroarylation step and an efficient
[4+2]/retro-[4+2] sequence.
R1
O
Ar2
O
O
R1
P(R2)2
i-Pr
P
P
MeO
MeO
P(Ar)2
P(Ar)2
CuX
Ar2
i-Pr
L3: BrettPhos
(R1: OMe, R2: Cy)
L4: XPhos
(R1: H, R2: Cy)
L5: t-BuBrettPhos
O
P1: X = OAc
P2: X = Cl
L2:
i-Pr
Ar= 3,5-(t-Bu)2-4-MeOC6H2 Ar= 3,5-(t-Bu)2-4-MeOC6H2
(S)-DTBM-SEGPHOS (L1) (R)-DTBM-OMe-BIPHEP
(R1: OMe, R2: t-Bu)
aReaction conditions: 0.2 mmol styrene (1.0 equiv), yields were
determined by 1H NMR spectroscopy of the crude reaction
mixture, using 1,1,2,2-tetrachloroethane as internal standard.
Enantiomeric ratio (er) was determined by chiral SFC. nd: not
determined
more efficient in the hydrofunctionalization reaction than the
corresponding hetereoaryl bromide, use of 2c in the current process
resulted in minimal olefin hydrocyanation (entry 10). A variety of
acetylene diester derivatives, such as the di-n-octyl substituted ester
(7b), performed well as dienophiles. Notably, the judicious choice
of dienophile coupling partner aided in the purification of the nitrile
products (see below and the Supporting Information for details).
Having established appropriate reaction conditions for the
asymmetric olefin hydrocyanation reaction, we investigated the
scope of vinyl arene substrates (Scheme 1). Vinyl arenes bearing a
substituent at the para-position, such as phenyl (3b), isobutyl (3d),
or thiomethyl (3e), were well tolerated under the reaction
conditions, resulting in good yields and enantioselectivity of the
nitrile product. Facile enantiospecific hydrolysis could convert
nitrile 3d and 3g to ibuprofen10 and cicloprofen,14 respectively,
both of which are nonsteroidal anti-inflammatory drugs
(NSAIDs).23 A vinyl arene containing ortho-substitution was
effectively converted to the nitrile (3c) in high yield and
enantiopurity. Moreover, substrates containing heterocycles,
including benzofuran (3f), indoline (3h), N-tosyl-indole (3i),
carbazole (3j), pyrazole (3k), morpholine (3m), and N-Boc-
piperzine (3o), were smoothly transformed to the nitrile product
with excellent selectivity. Additionally, 1,2-disubstituted alkenes
(Scheme 1B), a problematic substrate class for complementary Ni-
catalyzed asymmetric olefin hydrocyanation methods,7h performed
well under our reaction conditions (3l and 3m). However, cyclic
olefins were difficult substrates for this transformation. Nitrile 3n
was isolated in moderate yield and enantioselectivity when 1n was
subjected to the standard catalytic system. We hypothesized that
this diminished yield may reflect a slower rate of transmetallation
between the proposed organometallic species II and IV, potentially
due to a more sterically congested transition state, or a slower rate
of hydrocupration of 1n. To further highlight the applicability of
this formal olefin hydrocyanation method to access medicinally
relevant molecules, we synthesized an intermediate (3o) en route to
8, a USP28 inhibitor (Scheme 1C). Conversion of 3o to 8 could be
achieved via reduction of the nitrile (3o) and acylation of the
resulting primary amine.24
Accordingly, we focused on finding a suitable halo-oxazole
coupling partner (2) and a set of experimental reaction conditions
for the asymmetric olefin hydrocyanation using styrene (1a) as a
model substrate (Table 1). Our investigation of the optimal reaction
conditions identified oxazole 2a as an excellent nitrile surrogate
and the commercially available alkyne 7a as a suitable dienophile.
When 2a and 7a were utilized in conjunction with
[Pd(cinnamyl)Cl]2, BrettPhos (L3), P1, NaOTMS, and
Me2(Ph)SiH, the desired nitrile 3a was formed in high yield and
enantioselectivity (entry 1, 96% 1H NMR yield and 97:3 er),
without isolation of the alkyl oxazole intermediate (4). Evaluation
of a series of Cu salts and chiral bisphosphines (entries 1–5) led us
to discover the air-stable Cu(I) precatalyst P1, which enabled the
reaction to be set up without the use of an inert-atmosphere
glovebox.22 Use of the previously described (S)-DTBM-
SEGPHOS-ligated CuCl precatalyst P218b formed the desired
product in similar yield but with considerably lower
enantioselectivity (entry 2). Variation of the biarylphosphine
backbone (entries 6–7) or the absence of a Pd-catalyst (entry 8)
resulted in diminished yield or no product formation respectively.
Examination of an alternative to 2a as the nitrile surrogate
highlighted the crucial role of the oxazole substituents in this
transformation. Modification of the substituent at the 5-position
from methyl to phenyl (2b) delivered nitrile 3a in considerably
lower yield and enantioselectivity, presumably due to the electron-
poor nature of the corresponding alkyl oxazole intermediate (entry
9). While our previous reports on enantioselective olefin
hydroarylation18b suggested that a 2-chloro-N-heterocycle was
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Scheme 1. Substrate scope of the asymmetric Markovnikov
hydrocyanation of vinyl arenes. a
Scheme 2. Substrate scope for the anti-Markovnikov
hydrocyanation of unactivated olefins.a
i. rac-P1 (6.0 mol%), Me2PhSiH (2.0 equiv)
1
2
3
4
5
6
i. P1 (6.0 mol%), Me2PhSiH (2.0 equiv)
NaOTMS (2.0 equiv), BrettPhos (6.0 mol%)
[Pd(cinnamyl)Cl]2 (6.0 mol% [Pd]),
THF [0.6], 45 ºC, 16 h
NaOTMS (2.0 equiv), BrettPhos (6.0 mol%)
Me
Me
O
N
CN
[Pd(cinnamyl)Cl]2 (6.0 mol% [Pd])
THF [0.6], 45 ºC, 16 h
O
Ph
R
R
Ph
CN
Ar
Ar
RO2C
CO2R
(3.5 equiv)
ii.
R
R
N
(7b)
CO2n-Oct
PhMe [4.0], 110 ºC, 8 h
Br
ii. n-OctO2C
Br
R: Et (7a), n-oct (7b)
PhMe [4.0], 110 ºC, 8 h
1
2a
(1.3 equiv)
3
9
2a
10
(1.0 equiv)
(1.0 equiv)
(1.5 equiv)
A. Vinyl (hetero)arenes
CN
7
8
9
F
O
CN
Me
CN
CN
CN
CN
Et
O
Me
Me
Me
Me
Me
MeO
Me
O
Me
Ph
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
MeS
10a
75%
10b
73%
3b
3cc
96% yield
96:4 er
3d
71% yield
99:1 er
3ed
80% yield
89:11 er (91:9 er)b
74% yield
85:15 er (96:4 er)b
O
O
Me
CN
CN
CN
CN
CN
Me
Me
N
Me
Me
O
Me
10db
79%
10c
75%
3f
3g
3h
72% yield
97:3 er
O
CN
N
N
CN
Me
70% yield
85:15 er
72% yield
94:6 er
S
CN
CN
Me
Me
CN
10f
73%
10e
71%
F
Me
N
N
N
O
O
N
N
N
CN
Ts
N
Ph
N
3id
46% yield
98:2 er
3j
3k
74% yield
97:3 er
O
N
O
N
Cy
53% yield
99:1 er
Bn
H
Cilostazol (11)
10gc
59%
B. 1,2-disubstituted alkenes
CN
aAll yields represent the average of isolated yields from two runs
purified by silica flash chromatography with 0.5 mmol alkene.
CN
F3C
n-Pr
CN
OBn
O
bYield was determined by H NMR spectroscopy using 1,1,2,2-
N
1
O
tetrachloroethane as an internal standard c4.0 mol% P1
3le
73% yield
99:1 er
3md,f
62% yield
99:1 er
3n
34% yield
89:11 er
regioselective hydrocyanation of terminal olefins without
significantly modifying the standard reaction conditions (Scheme
2). Overall, this process tolerates the presence of a variety of
important structural elements (10a–10g), including an ester (10b),
dioxolane (10c), benzothiazole (10e), indole (10f) and an amide
(10g). Furthermore, the corresponding alkyl nitriles were isolated
in high yield and regioselectivity. Hydrocyanation of terminal
alkene (9d) accentuated the degree of chemoselectivity for this
process, which generated 10d in good yield without any detectable
hydrocyanation of the trisubstituted alkene. We further
demonstrated the utility of this method by synthesizing the nitrile
derivative (10g) of the cardiovascular drug Cilostazol (11), which
could conceivably be converted to 11 following deprotection and
tetrazole formation.26 As previously mentioned, reduction of the
halo-oxazole (2) and the olefinic coupling partner represents
potential side reactions for this transformation. Formation of a
significant amount of reduced 9g was observed when the olefin was
subjected to the standard reaction conditions. A decrease in the
amount of P1 utilized, from 6.0 to 4.0 mol%, was necessary to
improve the efficiency of the dual CuH/Pd catalytic system and
deliver amide 10g as the major product.
C. Synthesis of pharmaceutical intermediate
H2N
Me
N
O
S
NH
CN
ref. 24
Me
Me
N
N
3o
64% yield
96:4 er
N
HN
tBuO2C
USP28 inhibitor (8)
aAll yields represent the average of isolated yields from two runs
purified by silica flash chromatography with 0.5 mmol alkene;
alkyne (7b) was used unless otherwise noted, enantioselectivity
determined by chiral SFC or HPLC. bAlternative purification was
used, see supporting information for details. cYield was
determined by 1H NMR spectroscopy using 1,1,2,2-
tetrachloroethane as an internal standard due to the volatility of the
product. Alkyne (7a) was used. Intermediate oxazole 4l was
purified, isolated yield reported over two steps. 1.5 equiv of 2a
and 24 h at 45 ºC
d
e
f
We were interested in extending this chemistry toward the anti-
Markovnikov hydrocyanation of unactivated olefins, which can
Enantioenriched alkyl nitriles (3) often undergo epimerization or
decomposition under a variety of acidic, basic and oxidative
conditions, thus making further manipulation of the resulting nitrile
product potentially challenging.7f,28 To obviate these degradation
pathways, we envisioned that the chiral alkyl oxazole (4) may serve
as a stable masked nitrile in multistep organic synthesis, which
could be revealed at a later stage under neutral reaction conditions
(Scheme 3). To illustrate this concept, we employed 1,2-
disubstituted olefin 1p as a simple representative example. An
initial asymmetric olefin hydroarylation reaction installed the
often be
a synthetic challenge due to competitive olefin
isomerization.5,27 Several approaches to alkyl nitriles have been
developed to circumvent these undesired pathways, such as
dehydration of amides, oxidation of primary amines,
or
nucleophilic substitution of alkyl halides.4b In line with our
previous work,18b we anticipated the anti-Markovnikov
hydrocyanation to be more challenging due to the higher
hydrocupration barrier.25 However, we were able to perform the
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Journal of the American Chemical Society
Page 4 of 6
oxazole substructure (4p), which was followed by silyl group
1
2
3
4
5
6
7
8
Notes
Scheme 3. Enantioenriched oxazoles as masked nitriles in
The authors declare the following competing financial
interest(s): MIT has obtained patents for some of the ligands
that are described in this Communication from which S.L.B.
and former/current co-workers receive royalty payments.
multistep synthesis
Ph
O
1. P1 (6.0 mol%), Me2PhSiH (2.0 equiv)
NaOTMS (2.0 equiv), BrettPhos (6.0 mol%)
[Pd(cinnamyl)Cl]2 (6.0 mol% [Pd]), 16 h
N
Me
Me
Me
53% yield, 99:1 er
ACKNOWLEDGMENT
TBSO
TBSO
1p
4p
Research reported in this publication was supported by the
Arnold and Mabel Beckman Foundation for a postdoctoral
fellowship to A.W.S., the Swiss National Science Foundation
(SNSF) for a postdoctoral fellowship (P2GEP2-181266) to
G.M.B.-C. and the National Institutes of Health (R35-
GM122483 and F32-GM131633 to A.W.S.). We thank the
National Institutes of Health for a supplemental grant for the
purchase of supercritical fluid chromatography (SFC)
equipment (GM058160-17S1). We thank Sigma-Aldrich for
the generous donation of XPhos and BrettPhos ligands. We
are grateful to Drs. Richard Liu, Scott McCann, and Christine
Nguyen for advice on the preparation of this manuscript.
OMe
OMe
2.TBAF
or HCl
3. NaH
BnBr
89% over
2 steps,
>99:1 er
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
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Ph
N
O
CN
Me
Me
4. n-OctO2C
CO2n-Oct
Me
7b (3.5 equiv)
PhMe [4.0], 110 ºC, 8 h
84% yield, >99:1 er
BnO
BnO
3p
4p’
OMe
OMe
aReagents and conditions: (1) Average of isolated yields from
two runs on 0.5 mmol scale; (2) TBAF (1.5 equiv), THF [0.45],
rt, 1.5 h or aq. 6 M HCl (5.0 equiv), THF [0.5], rt, 16 h; (3) NaH
(1.2 equiv), BnBr (1.2 equiv), rt, 18 h, 89% or 81% over two
steps, respectively >99:1 er; (4) 7b (3.5 equiv), PhMe [4.0], 110
ºC, 8 h, 84%, >99:1 er
REFERENCES
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removal, either under acid or fluoride-mediated conditions, and
basic functionalization of the resulting phenol to yield oxazole 4p’
without any erosion of the enantioselectivity. A subsequent thermal
cycloaddition sequence with alkyne 7b revealed the nitrile (3p)
with complete enantiospecificity. We believe that this strategy will
be further applicable in more sophisticated contexts and numerous
reaction manifolds that would otherwise result in decomposition of
the nitrile substructure.
In summary, we have developed an asymmetric olefin
hydrocyanation sequence that relies on an oxazole as surrogate for
a nitrile, thus avoiding the use of any sources of cyanide in the
reaction mixture. These reaction conditions developed were
broadened to the anti-Markovnikov hydrocyanation of unactivated
olefins. We anticipate that this strategy of employing an
enantioenriched alkyl oxazole as a masked nitrile in multistep
synthesis will find further utility in a variety of scenarios.
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ASSOCIATED CONTENT
Supporting Information.
The Supporting Information is available free of charge on the
ACS Publications website. Experimental procedures, and
characterization data for all new compounds including 1H- and
13C-NMR spectra, SFC and HPLC traces (PDF).
AUTHOR INFORMATION
Corresponding Author
Alkynes
Using
1‑Methylcyclohexa2,5-diene-1-
*E-mail: sbuchwal@mit.edu
carbonitrile. J. Am. Chem. Soc. 2018, 140, 16353–16359.
(e) Orecchia, P.; Yuan, W.; Oestreich, M. Transfer
Hydrocyanation of α- and α,β-Substituted Styrenes
Catalyzed by Boron Lewis Acids. Angew. Chem. Int. Ed.
2019, 58, 3579–3583.
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hydrocyanation, see: (a) Elmes, P. S.; Jackson, W. J.
Asymmetric addition of hydrogen cyanide to alkenes
catalyzed by a zerovalent palladium compound. J. Am.
Chem. Soc. 1979, 101, 6128–6129. (b) RajanBabu, T. V.;
Author contributions
†A.W.S. and G.M.B.-C. contributed equally.
ORCID
Alexander W. Schuppe: 0000-0001-6002-9110
Stephen L. Buchwald: 0000-0003-3875-4775
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Dispersion
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O
O
CN
N
Br
N
R2
Cu
Pd
*
R1
R2
R2
*
R1
R1
masked nitrile
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