Nickel-Catalyzed Asymmetric Reductive Cross-Coupling between Heteroaryl Iodides and α-Chloronitriles

Article abstract of DOI:10.1021/jacs.5b06466

A Ni-catalyzed asymmetric reductive cross-coupling of heteroaryl iodides and α-chloronitriles has been developed. This method furnishes enantioenriched α,α-disubstituted nitriles from simple organohalide building blocks. The reaction tolerates a variety of heterocyclic coupling partners, including pyridines, pyrimidines, quinolines, thiophenes, and piperidines. The reaction proceeds under mild conditions at room temperature and precludes the need to pregenerate organometallic nucleophiles.

Full text of DOI:10.1021/jacs.5b06466

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Communication
Nickel-Catalyzed Asymmetric Reductive Cross-Coupling
between Heteroaryl Iodides and #-Chloronitriles.
Nathaniel T. Kadunce, and Sarah E. Reisman
J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 09 Aug 2015
Downloaded from http://pubs.acs.org on August 9, 2015
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Nickel-Catalyzed Asymmetric Reductive Cross-Coupling
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between Heteroaryl Iodides and α-Chloronitriles.
Nathaniel T. Kadunce and Sarah E. Reisman*
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The Warren and Katharine Schlinger Laboratory for Chemistry and Chemical Engineering, Division of Chemistry and Chemical En-
gineering, California Institute of Technology, Pasadena, CA 91125, United States.
Supporting Information Placeholder
ABSTRACT: A Ni-catalyzed asymmetric reductive cross-
coupling of heteroaryl iodides and α-chloronitriles has been
developed. This method furnishes enantioenriched α,α-
disubstituted nitriles from simple organohalide building
blocks. The reaction tolerates a variety of heterocyclic cou-
pling partners, including pyridines, pyrimidines, quinolines,
thiophenes, and piperidines. The reaction proceeds under
mild conditions at room temperature, and precludes the
need to pre-generate organometallic nucleophiles.
coupling methods to directly prepare enantioenriched α,α-
disubstituted nitriles. In 2010, Falck and coworkers pub-
lished a Pd-catalyzed stereospecific Suzuki cross-coupling of
8
α-cyanohydrin triflates. Two years later, Fu and Choi re-
ported a highly enantioselective Ni-catalyzed Negishi cou-
pling between racemic α-bromonitriles and arylzinc rea-
9
,10
gents. However, neither report included heteroaryl nucle-
ophiles as part of their substrate studies.
Scheme 1. Transition metal-catalyzed cross-coupling reac-
tions of α-cyano electrophiles.
a) Pd-catalyzed stereospecific Suzuki cross-coupling of !-cyanohydrin triflates.
In recent years, Ni-catalyzed reductive cross-coupling re-
actions have experienced a surge of development. These
(Falck, 2010)
1
PdL Cl2 (5 mol %)
KF (4 equiv)
2
NMe2
CN
OTf
CN
L:
+
R B(OH)
transformations forge C–C bonds between two organic elec-
2
2
H2O (4 equiv)
PhMe, rt
tBu2P
R1
R1
R
0
R = aryl
trophiles, employing a stoichiometric reductant (usually Zn
0
or Mn ) to turn over the Ni catalyst. An appealing aspect of
b) Ni-catalyzed enantioselective Negishi cross-coupling of !-bromonitriles.
(Fu, 2012)
this chemistry is that sec-alkyl electrophiles are competent
NiCl2(dme) (10 mol %)
iPr(cPent)BOX (13 mol %)
CN
2
CN
+
O
O
reaction partners, and in some cases, these reactions can be
R Zn
2
R1
R
TMEDA (20 mol %)
THF, –78 °C
N
N
rendered enantioselective by use of an appropriate chiral
R1
Br
R = alkenyl
or aryl
(±)
iPr
iPr
3
3
ligand. However, the scope of C(sp ) electrophiles used in
these asymmetric transformations has so far been limited to
i
c
Pr( Pent)BOX
This work: Ni-catalyzed enantioselective reductive cross-coupling between
!-chloronitriles and heteroaryl iodides.
α-substituted benzyl chlorides. Moreover, the asymmetric
cross-coupling of heteroaryl electrophiles – a substrate class
NiCl2(dme) (10 mol %)
DMMB-PhOX (20 mol %)
CN
CN
±)
I
O
4
that would be of high value for medicinal chemists – has
+
R1
Het
Ar2P
N
R1
0
Cl
Mn , TMSCl (40 mol %)
Het
5
proven challenging. In this communication, we report the
dioxane, rt
Bn
DMMB-PhOX
(
Ni-catalyzed asymmetric reductive cross-coupling between
α-chloronitriles and heteroaryl iodides, a reaction that pro-
vides access to a variety of enantioenriched heterocyclic
products.
We envisioned that a Ni-catalyzed asymmetric reductive
cross-coupling between α-chloronitriles and heteroaryl hal-
ides could provide access to a complementary scope of syn-
thetically useful products. Furthermore, α-chloronitriles
3
In considering the development of new C(sp ) electro-
3
philes for Ni-catalyzed reductive cross-coupling reactions,
we became interested in the use of α-chloronitriles. Nitriles
are valuable synthetic intermediates that serve as precursors
to amines, carboxylic acids, carboxamides, aldehydes, ke-
have not been developed as C(sp ) electrophiles for Ni-
catalyzed reductive cross-coupling reactions (even in the
1
1
racemic sense). Thus, the successful development of this
transformation would expand the scope of reductive cross-
coupling reactions to new and synthetically versatile classes
of electrophiles.
6
tones, and alcohols. The cyano group is also found in a
7
number of natural products and medicinal compounds.
However, there are few transition metal-catalyzed cross-
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Page 2 of 5
a
Table 1. Optimization of reaction conditions.
2 to a LNi(0) complex, relative to the rate of hydrodehalo-
genation and decomposition reactions of 1, thereby improv-
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
CN
1
2
ing the yield of 3a. Consistent with this hypothesis, phos-
phino-oxazoline (PhOX) ligands were found to provide im-
proved reactivity, with BnPhOX L5 furnishing 3a in 52%
yield and 77% ee (entry 7). Further ligand optimization
identified DMMB-PhOX L6 as providing the best combina-
tion of yield and selectivity (entry 1). A study of additional
Ph
2
NiCl2(dme) (10 mol % )
ligand (20 mol %)
CN
Cl
I
3
a
N
Ph
+
Mn0 (3.0 equiv)
TMSCl (40 mol %)
dioxane, rt, 14 h
+
2
N
CN
1
a
2
Ph
(
1.0 equiv)
(1.0 equiv)
H
2
4
0
reaction parameters revealed that: 1) use of Zn instead of
a
0
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Entry Ligand Deviation from Yield 3 Yield 4
ee 3
Mn provides the product in lower yield and ee (entry 12),
b
b
c
Standard Conditions (%)
(%)
(%)
84
--
and 2) 2-bromo-4-phenylbutanenitrile (5) suffers from fac-
ile hydrodehalogenation and elimination under the reaction
conditions, providing 3a in only 9% yield and 84% ee (entry
1
2
L6
L1
None
78
0
20
DMA instead of
dioxane
62
1
6). Additives that have been shown to improve the yields of
reductive cross-electrophile coupling were also investigated
3
4
5
6
7
8
9
L1
L2
L3
L4
L5
L6
L6
L6
--
--
<5
17
25
0
32
22
40
32
35
0
38
9
3a, 5a
(
entries 13–15).
comparable yield and improved selectivity (entry 14); how-
ever, further studies revealed that for many substrates, NaBF
provides no added benefits. Erring toward the use of fewer
reagents, NaBF was only added for the cross-coupling of
certain more challenging substrates, as indicated in the fol-
lowing Tables. The exact role of NaBF in these transfor-
4
The addition of NaBF provided 3 in
--
4
--
--
83
--
4
--
52
0
77
--
No Ni
4
5
a
0
mations is unknown at this time.
No Mn
0
0
--
Having optimized the reaction parameters for the coupling
between 1a and 2, we sought to probe the scope of the het-
eroaryl partner (Table 2). We were pleased to find that a
variety of heteroaryl iodides undergo cross-coupling to fur-
nish the α,α-disubstituted nitriles in good yields and with
high enantioinduction. The reaction demonstrates good
chemoselectivity, with no coupling observed at the 2-
position of 2-bromo- or 2-chloro-5-iodopyridine (see prod-
1
0
No TMSCl
<5
4
<5
23
32
37
24
29
36
82
0
11
No Ligand
0
0
1
1
1
1
2
3
4
5
L6 Zn instead of Mn
25
48
76
71
9
10
78
90
84
84
L6
L6 NaBF
L6 NaI (0.25 equiv)
TFA (0.4 equiv)
4
(1.0 equiv)
16
L6 RBrCN (5) instead
of 1
13
ucts 7a and 7b). Whereas substitution meta to the iodide
was tolerated (7f), a decrease in yield was observed when
the substituent was ortho to the iodide (7g). Iodo-pyridines
or -pyrimidines lacking substitution at C2 were poor sub-
strates, presumably due to the increased Lewis basicity of the
nitrogen. A variety of C2-substituted pyrimidines, as well as
a
Reactions conducted under inert atmosphere on 0.1 mmol
scale for 14 h. Determined by H NMR versus an internal
standard. Determined by SFC using chiral stationary phase.
b
1
c
Me Me
2
-iodothiophene and a 6-imidazopyridine also undergo
O
O
O
O
cross-coupling, delivering products in good yield and with
high enantioinduction (7h–7o). Importantly, many of the
products were easily recrystallized to afford highly enanti-
oenriched (>95% ee) material with excellent recovery. For
less-reactive heteroaryl iodides, competitive hydrodehalo-
genation of 1a resulted in decreased yields; this could be
mitigated in most cases by using two equivalents of the io-
N
N
PPh2 N
PAr2
N
Ph
L1
L2
Ph
R
Bn
O
O
L6
i
L3 R= Pr
DMMB-PhOX
Ar = 3,5-dimethyl-
4-methoxyphenyl
t
L4 R= Bu
iPr
N
N
iPr
L5 R= Bn
We began our investigations with the coupling between α-
chloronitrile 1a and 3-iodoquinoline (2). When the reaction
was conducted in DMA with chiral BOX ligand L1 and
14
dide partner.
0
TMSCl to activate Mn , no product was formed (Table 1,
We also investigated the scope of the α-chloronitrile (1).
In general, less sterically-encumbered substrates provide
products in good yield and modest enantioselectivity, while
more bulky substrates provide the product with good enan-
tioselectivity and slightly more modest yields. Nonetheless,
the reaction exhibits notable functional group tolerance, in-
cluding carbamates (3h and 3i), esters (3f) and a primary
alkyl chloride (3g). Recrystallization of nitrile 3e provided
entry 2). Rather, the α-chloronitrile was rapidly consumed,
generating the hydrodehalogenation product 4-
phenylbutyronitrile (4). A solvent screen revealed that 3a
forms in trace yield and 38% ee when dioxane is used as sol-
vent (entry 3); chiral BiOX ligand L2 provided slightly im-
proved yield (entry 4). We hypothesized that more electron-
rich ligands might accelerate the rate of oxidative addition of
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crystals suitable for X-ray diffraction analysis, which allowed
15
us to assign the stereochemistry as the (S)-configuration.
radical pathway, cyclopropyl-containing substrate 11 was
prepared and subjected to the reaction conditions (Scheme
). Ring-opened coupling product 12 was obtained in 21%
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
3
yield as a 1:1 mixture of cis and trans isomers, consistent with
a
a
Table 2. Scope of heteroaryl iodide.
Table 3. Scope of α-chloronitriles.
NiCl2(dme) (10 mol %)
L6 (20 mol %)
CN
CN
Cl
1.0 equiv)
NiCl2(dme) (10 mol %)
CN
I
CN
Ph
(
+
Het
Ph
L6 (20 mol %)
Mn0 (3 equiv)
TMSCl (40 mol %)
dioxane, rt, 18 h
+
2
I
2
Mn0 (3 equiv)
TMSCl (40 mol %)
dioxane, rt, 18 h
Het
R
Cl
R
1
a
6a–o
(1.0 equiv)
7a–o
N
1a–i
1.0 equiv)
2
3a–i
N
(
(1.0 equiv)
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
CN
CN
Me
CN
CN
CN
tBu
Ph
N
Cl
N
Br
N
CF3
N
7d
OMe
Me
Me
Bn
2
7
a
7b
7c
3
a
3b
3c
3d
3e
68% yieldc
70% yieldc
45% yieldb,c
8
2% yield
88% ee
c
c
c
7
2% yield
2% ee
79% yield
81% ee
65% yield
89% ee
45% yield
93% ee
65% yield
90% ee
88% ee
85% ee
F
83% ee
9
(57% yield, 96% ee)
F
N
N
CN
CN BocN
CN
CN
N
N
Cl
EtO
N
F
Cl
7e
7f
7g
7h
O
BocN
4% yieldb,c
60% yieldc
3f
3g
3h
3i
6
37% yield
83% ee
41% yield
89% ee
b
8
7% ee
79% ee
63% yield
0% ee
78% yield
79% ee
61% yield
89% ee
41% yield
91% ee
8
N
N
N
N
a
Reaction conducted on 0.2 mmol scale. Isolated yields are
provided; ee is determined by SFC using chiral stationary phase.
Values in parentheses are yield and ee following a single recrys-
N
OMe
N
SPh
N
N
N
N
7
i
7j
7k
7l
7
1% yieldb,c
76% yield
91% ee
70% yield
85% ee
60% yield
86% ee
b
c
tallization of the product. 2.0 equiv heteroaryl iodide used. 1
equiv NaBF added.
9
2% ee
4
(62% yield, 95% ee) (54% yield, 97% ee)
S
Scheme 2. Derivatization of α,α-disubstituted nitriles.
N
N
Br
N
N
N
NHBoc
Boc2O
1.5 equiv)
Raney Ni
7
m
NBoc
7n
7o
(
69% yield
5% ee
87% yield
88% ee
72% yieldb
N
8
87% ee
H2 (1 atm)
N
N
(62% yield, 94% ee)
(63% yield, 97% ee)
8
2
3 ºC, 12 h
9
5% yield
8
5% ee
a
Reaction conducted on 0.2 mmol scale. Isolated yields are pro-
7k
85% ee
H2N
O
vided; ee is determined by SFC using chiral stationary phase. Val-
ues in parentheses are yield and ee following a single recrystalli-
Ghaffar–Parkins
catalyst
(20 mol %)
N
b
c
zation of the product. 2.0 equiv heteroaryl iodide used. 1.0
equiv NaBF added.
EtOH, H2O
N
O
N
6
5 ºC, 36 h
9
4
95% yield
5% ee
8
The enantioenriched α,α-disubstituted nitriles produced
in this reaction serve as versatile synthetic intermediates. For
example, hydrogenation of 2-piperidyl-pyrimidine 7k under
standard conditions provides phenethylamine 8 in excellent
yield and with no erosion of ee (Scheme 2). The two step
sequence involving cross-coupling and hydrogenation repre-
sents an straightforward approach to the synthesis of this
bioactive class of molecule. The same substrate can be sub-
H
DIBAL-H (3 equiv)
S
7
n
88% ee
CH2Cl2, –41 ºC
20 min
10
6% yield
81% ee
9
17
a radical intermediate. None of the corresponding cyclo-
propane-containing product was observed. Despite this evi-
dence for a radical intermediate, the reaction proceeds with
comparable efficiency in the presence of 50 mol % of com-
mon radical inhibitors, such as 2,6-bis(1,1-dimethylethyl)-4-
16
jected to Pt-catalyzed hydrolysis to afford carboxamide 9 in
high yield and with complete stereoretention. Alternatively,
reduction of thiophene-containing nitrile 7n with DIBAL-H
furnished the enantioenriched aldehyde 10 in excellent yield
and with minor erosion of ee.
18
methylphenol (BHT) or dihydroanthracene (DHA). The
latter finding is inconsistent with cage-escaped radicals ex-
pected in a radical chain mechanism, although more studies
Several experiments were conducted to interrogate the po-
tential mechanism of this transformation. To probe whether
1
9
are needed to fully elucidate the reaction pathway.
the oxidative addition of the α-chloronitrile proceeds by a
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Journal of the American Chemical Society
In conclusion, a Ni-catalyzed asymmetric reductive cross-
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coupling between α-chloronitriles and heteroaryl iodides has
been developed. A new chiral PHOX ligand was identified
that provides α,α-disubstituted nitriles in good yields and
with high enantioinduction. This is the first example of a Ni-
catalyzed asymmetric reductive cross-coupling reaction that
tolerates N- and S- heterocyclic coupling partners, and
demonstrates the feasibility of developing related transfor-
mations of electrophiles containing Lewis basic functional
groups. The development of new asymmetric reductive
cross-coupling reactions as well as mechanistic investigations
are the subject of ongoing research in our laboratory.
A.; Martin, R. Chem. Eur. J. 2014, 20, 8242; (d) Weix, D. J. Acc. Chem.
Res. 2015.
(2) (a) Durandetti, M.; Gosmini, C.; Périchon, J. Tetrahedron, 2007, 63,
1146; (b) Everson, D. A.; Shrestha, R.; Weix, D. J. J. Am. Chem. Soc. 2010,
1
1
32, 920; (c) Yu, X.; Yang, T.; Wang, S.; Xu, H.; Gong, H. Org. Lett. 2011,
3, 2138; (d) Wotal, A. C.; Weix, D. J. Org. Lett. 2012, 14, 1476; (e) Wu,
F.; Lu, W.; Qian, Q.; Ren, Q.; Gong, H. Org. Lett. 2012, 14, 3044.
3) (a) Cherney, A. H.; Kadunce, N. T.; Reisman, S. E. J. Am. Chem. Soc.
(
2013, 135, 7442; (b) Cherney, A. H.; Reisman, S. E. J. Am. Chem. Soc.
2014, 136, 14365; (c) Ackerman, L. K.; Anka-Lufford, L. L.; Naodovic,
M.; Weix,D. J. Chem. Sci. 2015, 6, 1115.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(
4) For analyses of heterocycles in drug candidates, see: (a) Roughley, S. D.;
Jordan, A. M. J. Med. Chem. 2011, 42, 3451; (b) Vitaku, E.; Smith, D. T.;
Njardarson, J. T. J. Med. Chem. 2014, 57, 10257
Scheme 3. Mechanistic experiments.
(
5) The asymmetric Ni-catalyzed reductive cross-coupling of (E)-2-(2-
bromovinyl)furan is the only previously reported example of a heterocyclic
substrate (see ref. 3b). For examples of non-asymmetric Ni-catalyzed re-
ductive cross-coupling of heterocyclic electrophiles, see: (a) Molander, G.
A.; Traister, K. M.; O'Neill, B. T. J. Org. Chem. 2014, 79, 5771; (b)
Molander, G. A.; Traister, K. M.; O'Neill, B. T. J. Org. Chem. 2015, 80,
2907; (c) Wang, S.; Qian, Q.; Gong, H. Org. Lett. 2012, 14, 3352; (d)
Molander, G. A.; Wisniewski, S. R.; Traister, K. M. Org. Lett 2014, 16,
a) Coupling of a radical clock substrate.
NiCl2(dme) (10 mol % )
Cl
S
S
L6 (20 mol %)
+
I
CN
Mn0 (3.0 equiv)
NC
TMSCl (40 mol %)
dioxane, rt, 14 h
1
1
6n
(1.0 equiv)
12
21% yield
: 1 E : Z
(
1.0 equiv)
1
3
(
692.
6) Science of Synthesis; Murahashi, S.-I., Ed.; Georg Thieme Verlag:
Stuttgart, Germany, 2004; Vol. 19.
b) Reaction in the presence of radical inhibitors.
NiCl2(dme) (10 mol % )
CN
Cl
I
L6 (20 mol %)
Ph
(
7) (a) Fleming, F. F. Nat. Prod. Rep.1999, 16, 597. (b) Fleming, F. F.; Yao,
L.; Ravikumar, P. C.; Funk, L.; Shook, B. C. J. Med. Chem. 2010, 53,
7902.
Ph
+
CN
Mn0 (3.0 equiv)
TMSCl (40 mol %)
dioxane, rt, 14 h
2
2
N
1
a
2
3a
N
(
1.0 equiv)
(1.0 equiv)
(8) He, A.; Falck, J. R. J. Am. Chem. Soc. 2010, 132, 2524.
no additive:
72% yield, 84% ee
66% yield, 83% ee
74% yield, 83% ee
(
(
9) Choi, J.; Fu, G. C. J. Am. Chem. Soc. 2012, 134, 9102.
5
0 mol % DHA:
50 mol % BHT:
10) MacMillan and coworkers recently reported an enantioselective cross-
coupling of primary α-bromonitriles with aldehydes under photoredox
organocatalysis. Welin, E. R.; Warkentin, A. A.; Conrad, J. C.; MacMillan,
D. W. C. Angew. Chem. Int. Ed. DOI: 10.1002/anie.201503789
ASSOCIATED CONTENT
Supporting Information. Detailed experimental proce-
dures, compound characterization data, H and C NMR spec-
tra. This material is available free of charge via the Internet at
http://pubs.acs.org.
(11) For a single example of a Ni-catalyzed electrochemical cross-coupling
1
13
of 2-chloropropanenitrile and (E)-(2-bromovinyl)benzene, see: Cannes,
C.; Condon, S.; Durandetti, M.; Perichon, J.; Nedelec, J.-Y. J. Org. Chem.
2000, 65, 4575.
(
12) Hartwig, J. F. Organotranisition Metal Chemistry; University Science
Books: Mill Valley, CA, 2010.
AUTHOR INFORMATION
(13) This chemoselectivity is notable given these prior reports of Ni-
catalyzed reductive cross-couplings of 2-chloropyridines: (a) Gosmini, C.;
Bassene-Ernst, C.; Durandetti, M. Tetrahedron. 2009, 65, 6141; (b)
Everson, D. A.; Buonomo, J. A.; Weix, D. J. Synlett. 2014, 25, 233.
Corresponding Author
*reisman@caltech.edu
(
14) Electron deficient (non-hetero) aryl iodides are also competent cou-
ACKNOWLEDGMENT
pling partners, providing the products in good yields but more modest
enantioselectivity. For example, 1-iodo-4-(trifluoromethyl)benzene cou-
ples to 3a in 76% yield and 70 % ee.
We thank Prof. Brian Stoltz, Dr. Scott Virgil, and the Caltech
Center for Catalysis and Chemical Synthesis for access to ana-
lytical equipment. We also thank Dr. Alan Cherney and Robert
Scanes for helpful discussions. S.E.R. is a Camille Dreyfus
Teacher-Scholar and an American Cancer Society Research
Scholar. Financial support from NIH (GM111805-01), Amgen,
Novartis, and Eli Lilly is gratefully acknowledged.
(15) See Supporting Information.
(
16) (a) Ghaffar, T.; Parkins, A. W. Tetrahedron Lett. 1995, 36, 8657; (b)
Ghaffar, T.; Parkins, A. W. J. Mol. Catal. A: Chem. 2000, 160, 249.
17) Nonhebel, D. C. Chem. Soc. Rev. 1993, 5, 293.
(
(18) Addition of TEMPO to the reaction mixture results in poor conver-
sion, presumably from catalyst inhibition. There is no evidence of trapping
of carbon-based radicals.
(19) For mechanistic investigations of related Ni-catalyzed reactions, see:
(a) Ren, Q.; Jiang, F.; Gong, H. J. Organomet. Chem. 2014, 770, 130; (b)
Biswas, S.; Weix, D. J. J. Am. Chem. Soc. 2013, 135, 16192; (c) Gutierrez,
O.; Tellis, J. C.; Primer, D. N.; Molander, G. A.; Kozlowski, M. C. J. Am.
Chem. Soc. 2015, 137, 4896.
REFERENCES
(1) (a) Everson, D. A.; Weix, D. J. J. Org. Chem. 2014, 79, 4793; (b)
Knappke, C. E.; Grupe, S.; Gartner, D.; Corpet, M.; Gosmini, C.; Jacobi
von Wangelin, A. Chem. Eur. J. 2014, 20, 6828; (c) Moragas, T.; Correa,
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1
2
CN
±)
CN
I
Ni
R1
Cl
+
R1
Het
3
4
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7
8
9
1
1
1
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1
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5
5
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5
5
5
5
5
6
Het
(
Mn0
•
no pre-generated
organometallic reagents
up to 82% yield
and 93% ee
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
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6
7
8
9
0
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9
0
1
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0
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