Nickel-Catalyzed Cyanation of Unactivated Alkyl Chlorides or Bromides with Zn(CN)2

Article abstract of DOI:10.1021/acs.orglett.8b03539

A nickel-catalyzed cyanation of unactivated secondary alkyl chlorides or bromides using less toxic Zn(CN)₂ as the cyanide source has been developed. The reaction features the use of air-stable and inexpensive NiCl₂·6H₂O or Ni(acac)₂ as the precatalysts and offers an efficient synthesis of a broad range of alkyl nitriles. Cyanation of primary alkyl chlorides or bromides was also achieved by reaction with Zn(CN)₂ in the presence of n-Bu₄NCl without the need of nickel catalyst.

Full text of DOI:10.1021/acs.orglett.8b03539

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Nickel-Catalyzed Cyanation of Unactivated Alkyl Chlorides or
Bromides with Zn(CN)2
Aiyou Xia, Xin Xie, Haoyi Chen, Jidong Zhao, Chunli Zhang, and Yuanhong Liu*
State Key Laboratory of Organometallic Chemistry, Center for Excellence in Molecular Synthesis, Shanghai Institute of Organic
Chemistry, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 345 Lingling Lu, Shanghai 200032, People’s
Republic of China
S
* Supporting Information
ABSTRACT: A nickel-catalyzed cyanation of unactivated
secondary alkyl chlorides or bromides using less toxic
Zn(CN)2 as the cyanide source has been developed. The
reaction features the use of air-stable and inexpensive NiCl2·
6H2O or Ni(acac)2 as the precatalysts and offers an efficient
synthesis of a broad range of alkyl nitriles. Cyanation of
primary alkyl chlorides or bromides was also achieved by
reaction with Zn(CN)2 in the presence of n-Bu4NCl without
the need of nickel catalyst.
itriles are one of the most important building blocks for
modern organic synthesis. For example, they can serve as
precursors for amides, amines, carboxylic acids, aldehydes,
ketones, and alcohols, etc.1 Nitrile functionalities are also
frequently found in natural products, pharmaceuticals, and
agrochemicals2 (Figure 1). Alkyl nitriles have been prepared
hydride elimination of alkylmetal intermediates, proto-
demetalation, elimination of HX to form alkene byproducts,
etc.5 To the best of our knowledge, transition-metal-catalyzed
cyanation of alkyl halides has been limited mainly to benzyl
chlorides.6 In 2015, Fu and co-workers reported an excellent
work of photoinduced and copper-catalyzed cyanation of
unactivated alkyl halides with TBACN (tetrabutylammonium
cyanide) (Scheme 1).7 The method required special photo-
chemical equipment and expensive cyanating agent. Inspired
by our recent studies on nickel-catalyzed cyanation of aryl/
heteroaryl chlorides,4k we show here a mild, robust, and
efficient Ni-based catalytic system for cyanation of alkyl halides
using inexpensive and relatively less toxic Zn(CN)2 (intra-
N
Figure 1. Representative bioactive cyano-containing compounds.
Scheme 1. Transition-Metal-Catalyzed Cyanation of
Unactivated Alkyl Halides
classically by nucleophilic substitutions of alkyl halides or
pseudoalkyl halides with cyanide sources. However, in fact, the
studies on the cyanation of secondary alkyl halides are quite
rare, and the reported methods usually suffer from harsh
reaction conditions (high temperature, long reaction time) and
limited substrate scope.3 Besides, in most of the cases,
extremely poisonous NaCN or KCN was employed as the
cyanating agent. Thus, the development of cyanation of alkyl
halides using less toxic cyanating agents with high efficiency is
highly desired. In this regard, transition-metal-catalyzed cross-
coupling of alkyl halides with cyanide sources would be one of
the most powerful and promising methods for the synthesis of
alkyl nitriles. However, most research has focused on the
metal-catalyzed cyanation of aryl halides,4 while the cyanation
of alkyl halides to alkyl nitriles is considerably less developed.
This is possibly due to a number of challenges when alkyl
halides, especially alkyl chlorides, are used as the coupling
partners, such as a low tendency of oxidative addition, β-
Received: November 5, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b03539
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Table 1. Optimization of the Reaction Conditions
b
entry
catalyst
ligand
DMAP (equiv)
n-Bu4NCl (equiv)
solvent
yield (%)
c
1
2
3
4
5
6
7
8
NiCl2·6H2O
NiCl2·6H2O
NiCl2·6H2O
NiCl2·6H2O
NiCl2·6H2O
NiCl2(DME)
Ni(acac)2
NiCl2·6H2O
NiCl2·6H2O
NiCl2·6H2O
NiCl2·6H2O
NiCl2·6H2O
NiCl2·6H2O
NiCl2·6H2O
NiCl2·6H2O
NiCl2·6H2O
NiCl2·6H2O
NiCl2·6H2O
Xantphos
Xantphos
Xantphos
Xantphos
Xantphos
Xantphos
Xantphos
NiXantphos
dppf
2.0
0.5
0.5
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
DMF
86, 87
2 (97)
2 (98)
83 (6)
19 (78)
79
2.0
1.5
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
0.5
0.25
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
77
47 (40)
15 (76)
− (87)
− (97)
− (92)
− (99)
85 (2)
85
9
10
11
12
13
14
bipyridine
d
PCy3
d
PMePh2
e
Xantphos
Xantphos
Xantphos
Xantphos
Xantphos
Xantphos
Xantphos
f
g
15
16
17
18
19
20
78
THF
4 (94)
− (92)
− (96)
− (98)
toluene
CH3CN
CH3CN
NiCl2·6H2O
a
Conditions: 1a (0.5 mmol), Zn(CN)2 (0.4 mmol), Ni catalyst (0.025 mmol), ligand (0.025 mmol), zinc flakes (0.2 mmol), DMAP (1.0 mmol), n-
b
Bu4NCl (0.25 mmol) in solvent (1 mL) at 100 °C for 8 h. Determined by 1H NMR using 1,3,5-trimethoxybenzene as an internal standard. The
yields of recovered 1a are shown in parentheses. Isolated yield. 10 mol % of ligand was used. Mn (0.2 mmol) was used. 4-Aminopyridine was
used. n-Bu4NBr was used.
c
d
e
f
g
peritoneal, LD50 = 100 mg kg−1,8a compared with NaCN,
KCN,8b intraperitoneal, LD50 = 4.72−5.55 mg kg−1) as the
cyanating agent without the need for light. It was noted that
Zn(CN)2 has not been used as the coupling partner for the
cyanation of alkyl halides. The method exhibits a broad
substrate scope and can be successfully extended to the
efficient cyanation of alkyl bromides. The reaction also
represents the first example of thermally driven metal-catalyzed
cyanation of unactivated alkyl halides.
Initially, the nickel-catalyzed cyanation of a secondary alkyl
chloride 4-chloro-1-tosylpiperidine 1a was investigated. In-
spired by our previous results, Zn(CN)2 was chosen for the
alkyl coupling partner due to its low concentration of cyanide
ions in organic solvents, which is beneficial for mitigating
catalyst poisoning, and facile transmetalation of cyanide to the
arylnickel complex/reductive elimination to form Ar−CN in
the case of cyanation of aryl halides.4k As expected, under the
previously developed reaction conditions for the cyanation of
aryl halides (NiCl2·6H2O/dppf/Zn/DMAP/CH3CN/80
°C),4k trace desired nitrile 2a was observed (the starting
material was recovered in 96% yield). A thorough study of the
nickel catalyst, ligands, reductants, additives, solvents, and
substrate concentration, etc., was then performed, and the
detailed results are shown in the Supporting Information.
Finally, we found that the additives played important roles for
the reaction. The optimization conditions were briefly
summarized in Table 1. We were pleased to find that the
desired alkyl nitrile 2a could be formed smoothly in 86% yield
at 100 °C in CH3CN catalyzed by an inexpensive Ni(II)
source (NiCl2·6H2O) and the commonly used ligand of
Xantphos with a large bite angle (β = 111°) in the presence of
DMAP and n-Bu4NCl as the additives (Table 1, entry 1). Both
of DMAP and n-Bu4NCl were found to be the essential
additives for the successful transformation (entries 2 and 3),
and trace desired products were observed in the absence of the
either additive. The amount of n-Bu4NCl was also crucial for
this reaction, since decreasing the amount of this additive
resulted in significant erosion in yield (entry 5). Both DMAP
and n-Bu4NCl (vide infra) may have an effect on the activation
of Zn(CN)2 and promote the cyanide anion dissociation.
DMAP may also act as a co-ligand during the reaction
process.4k The catalytic activity of NiCl2(DME) and Ni(acac)2
was also investigated, which resulted in product yields of 77−
79% (entries 6 and 7). Other bidentate ligands such as
NiXantphos and dppf gave inferior yields, while the use of
monodentate phosphine ligands led to no desired product
(entries 8−12). Employing 4-aminopyridine or n-Bu4NBr as
the additive, the reaction could also take place effectively
(entries 14 and 15). Changing the solvent from CH3CN to
DMF afforded 2a in a lower yield of 78%, while the use of
other solvents such as THF and toluene gave either a low yield
or led to the recovery of the unreacted alkyl chloride (entries
16−18). It was noted that no desired reaction took place if
either the nickel catalyst or a ligand was absent (entries 19 and
20). The results indicated that nickel catalysis is operative in
this reaction process.
With the optimized reaction conditions in hand, we next
investigated the substrate scope for the cyanation of alkyl
halides. As shown in Scheme 2, the reaction proved to be quite
general for a wide variety of unactivated secondary alkyl
B
DOI: 10.1021/acs.orglett.8b03539
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
formed in 82% yield at 120 °C. When alkyl chloride derived
from natural products such as 1g was used as the substrate, the
desired product 2g was not observed, and most of the starting
materials remained unchanged. To our delight, increasing the
amount of n-Bu4NCl to 0.75 equiv with use of NiCl2 as the
catalyst under dilute reaction conditions resulted in the
formation of 2g in 48% yield. Heteroatom-containing
substrates such as N-benzyl-3-chloropyrrolidine were also
compatible, leading to 2h in 83% yield. Next, the cyanation
of a series of acyclic alkyl chlorides was investigated. Linear
substrates bearing methyl, ethyl, and even the more sterically
demanding isopropyl substituents could also be satisfactorily
cyanated, affording 2i−l in 61−89% yields. Substrate 1m
bearing two-branched cyclic rings provided the desired 2m in
48% yield, which could not be directly cyanated by TBACN
under thermal conditions.7 Other substrates such as (2-
chloropropane-1,3-diyl)dibenzene bearing two aryl rings or
ethers bearing various functional groups such as −F, −CN, or
−3,5-(MeO)2 on their phenyl rings were also suitable for this
reaction (2n−r). When alkyl chloride 1s bearing a ketone
functionality was employed as the substrate, only 17% yield
was obtained, along with the formation of various byproducts
under the standard reaction conditions. After some trails, we
were pleased to find that the desired nitrile could be formed in
70% yield catalyzed by a Ni(I) complex of [(dppf)NiICl]9 in
the presence of DMAP and n-Bu4NCl.
Scheme 2. Nickel-Catalyzed Cyanation of Unactivated
Secondary Alkyl Halides
a
Encouraged by the above results, we next attempted to
examine the possible Ni-catalyzed cyanation of alkyl bromides
3. During the studies, we found that the reaction proceeded
efficiently catalyzed by Ni(acac)2/Xantphos/DMAP/Zn at 80
°C without the need of adding n-Bu4NCl. Under these
optimized reaction conditions, various cyclic and acyclic alkyl
substrates converted to the desired nitriles smoothly (Scheme
2).
a
b
Applying the reaction conditions for secondary alkyl
chlorides to the coupling of primary alkyl chlorides such as
(3-chloropropyl)benzene 4a (see Scheme 3) with Zn(CN)2
Isolated yields. [Substrate] = 0.5 M. Under refluxing (oil bath
c
temperature: 130 °C). ((1S*,4S*)-4-Chlorocyclohexyl)benzene was
used. NiCl2(DME) and zinc power (100 mesh) were used instead of
NiCl2·6H2O and zinc flakes. 10 mol % of Ni(acac)2, 10 mol % of
Xantphos, 40 mol % of zinc flakes, 2.0 equiv of DMAP, 0.75 equiv of
n-Bu4NCl, 120 °C. NiCl2 was used instead of NiCl2·6H2O. 0.75
equiv of n-Bu4NCl was used instead of 0.5 equiv of n-Bu4NCl.
d
a
Scheme 3. Cyanation of Primary Alkyl Halides
e
f
[Substrate] = 0.25 M. Ni(acac)2 was used instead of NiCl2·6H2O. 90
g
h
°C, 12 h. [Substrate] = 1 M. 5 mol % of [(dppf)NiCl], 2.0 equiv of
i
DMAP, 0.75 equiv of n-Bu4NCl. 5 mol % Ni(acac)2, 5 mol % of
Xantphos, 2.0 equiv of DMAP, 40 mol % of zinc flakes, 80 °C, 12 h.
j
120 °C, 8 h.
chlorides, leading to the corresponding alkyl nitriles in
generally good to high yields within a short reaction time.
Cyclic substrates bearing six- or five-membered rings including
benzene-fused ones coupled smoothly with Zn(CN)2 (2b−d,
74−83% yields). It was noted that 2b was obtained in only
46% yield under the standard conditions. However, replacing
NiCl2·6H2O by NiCl2(DME) and using zinc powder as the
reductant improved the yield of 2b significantly. It was also
noted that 2b was obtained as a mixture of two diastereomers
from a single diastereomer of 1b. The results suggested that a
radical pathway might be involved in the course of oxidative
addition. Alkyl chlorides with a large-sized ring such as
chlorocyclododecane worked also well (2e). Polycyclic alkyl
chlorides such as 2-chloroadamantane gave only trace amounts
of the desired nitrile 2f. However, by switching the nickel
catalyst from NiCl2·6H2O to Ni(acac)2 and increasing the
amounts of both catalyst/ligand and n-Bu4NCl, 2f could be
a
b
Isolated yields. CH3CN was used as the solvent.
afforded 5a in only 32% yield. We postulated that a pyridinium
salt might be easily formed by the reaction of DMAP with
primary alkyl chloride,10 which may not act as an efficient
electrophile in this reaction. Indeed, treatment of 4a with
DMAP at 100 °C for 8 h followed at room temperature for 1 h
afforded the pyridinium salt 6 (4-(dimethylamino)-1-(3-
phenylpropyl)pyridinium chloride) in 69% yield.11 The desired
nitrile 5a was not observed by the reaction of 6 with Zn(CN)2
C
DOI: 10.1021/acs.orglett.8b03539
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
under the standard reaction conditions. By comparison, the
reaction of a secondary alkyl chloride 1a with DMAP was also
performed, as we expected, no pyridinium salt was formed in
CH3CN at 100 °C. To our delight, we found that cyanation of
primary alkyl chlorides could proceed effectively in the absence
of a nickel catalyst. For example, reaction of 4a with Zn(CN)2
in the presence of 2.0 equiv of n-Bu4NCl at 140 °C afforded
the nitrile 5a in 79% yield (without n-Bu4NCl, no reaction
occurred). Substrate 4b with a ketone functionality could be
cyanated at the lower reaction temperature (80 °C). Alkyl
chloride with an indole group or benzyl chloride could also be
successfully transformed into the corresponding nitriles (5c,
5d). These results also indicated that n-Bu4NCl played a role
in activation of Zn(CN)2 in the Ni-catalyzed reaction system.
It is considered that a zincate might be formed through the
coordination of chloride in n-Bu4NCl to Zn(CN)2, which
facilitates the cyanide dissociation.12 TBACl may also act as a
phase-transfer reagent. Similarly, primary alkyl bromides 7
including those bearing aryl, ether, and amide functionalities
were all smoothly cyanated (53−61%).
Xantphos, 2a was isolated in 15% yield). The ligand exchange
reaction might occur during the process. The above results
strongly support the NiI/NiIII reaction pathway.17
On the basis of the above observations, a mechanistic
proposal is depicted in Scheme 5. The reaction is initiated
Scheme 5. Possible Reaction Mechanism
To gain a mechanistic insight into this reaction, various
control experiments were performed. As shown in Scheme 4,
Scheme 4. Mechanistic Studies
through the formation of a LnNiI complex 8, which might be
generated through the comproportionation of the NiII species
with the in situ formed Ni0 intermediate.18 Complex 8
undergoes transmetalation with Zn(CN)2 leading to [LnNiI−
CN] species 9. This process is possibly accelerated by DMAP
and n-Bu4NCl through the formation of an adduct with
enhanced solubility and reactivity. Reduction of alkyl halide by
[LnNiI−CN] complex via a single-electron-transfer pathway
generates [LnNiIICN(X)] intermediate and an alkyl radical 10.
Subsequent recombination of the radical with NiII complex
delivers the NiIII complex 11. Reductive elimination of 11
provides the nitrile products 2 and regenerates the catalytically
active NiI species. Alternatively, complex 8 may first react with
alkyl halide through a radical process followed by trans-
metalation with Zn(CN)2 and reductive elimination.
In summary, we have developed the first thermally driven
nickel-catalyzed cyanation of unactivated secondary alkyl
halides with Zn(CN)2. The reaction features the use of air-
stable and inexpensive NiCl2·6H2O or Ni(acac)2 and common
ligand of Xantphos as the catalyst components and DMAP and
n-Bu4NCl as the additives, providing the alkyl nitriles with a
wide functional group tolerance. Preliminary mechanistic
studies indicate that a radical species might be generated
during the process and nickel(I) complex can also serve as an
efficient catalyst for this cyanation reaction. Cyanation of
primary alkyl chlorides or bromides was achieved by reaction
with Zn(CN)2 in the presence of n-Bu4NCl without the need
of nickel catalyst. Further investigations on the detailed
reaction mechanism and application of this chemistry are in
progress.
addition of a radical scavenger TEMPO (2,2,6,6-tetramethyl-
piperidin-1-oxyl) or BPE (1,1-diphenylethylene) inhibited the
reaction.13 Reductive cyclization/coupling of 3t14 with Zn-
(CN)2 under the standard conditions for cyanation of
secondary alkyl bromides afforded the cyclized product 2t
through 5-exo-trig ring closure in 33% yield. The diaster-
eoselectivity observed in this reaction correlates with that
observed in radical cyclization of the same substrate.15 These
results implied that radical intermediates might be involved in
the nickel-catalyzed cyanation process. By analogy to Ni-
catalyzed cross-coupling reactions of unactivated alkyl halides
with organometallic reagents such as organoboron and
organozinc reported by Fu et al.,16 we suggest here that an
alkyl radical and a NiII intermediate were generated through
the reaction of alkyl halides with a NiI species, which rapidly
combined to give an alkyl−NiIII complex. Then the NiI/NiIII
redox cycle might be a possible reaction pathway. In order to
probe the possible NiI/NiIII redox cycle, cyanation of 1a
catalyzed by [(dppf)NiICl] was investigated. It was found that
this NiI complex showed excellent catalytic activity to give 2a
in 89% yield in the presence of 10 mol % of Xantphos (without
ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b03539.
Experimental details and spectroscopic characterization
of all new compounds (PDF)
D
DOI: 10.1021/acs.orglett.8b03539
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Sun, Y.; Wang, J.; Ma, J.; Hou, C. Tetrahedron Lett. 2012, 53, 2825.
(c) Satoh, Y.; Obora, Y. RSC Adv. 2014, 4, 15736.
(7) Ratani, T. S.; Bachman, S.; Fu, G. C.; Peters, J. C. J. Am. Chem.
Soc. 2015, 137, 13902.
(8) (a) Patnaik, P. A Comprehensive Guide to the Hazardous
Properties of Chemical Substances, 3rd ed.; Wiley, 2006. (b) Hall, A. H.;
Isom, G. E.; Rockwood, G. A. Toxicology of Cyanides and Cyanogens:
Experimental, Applied and Clinical Aspects; Wiley, 2015.
(9) Yin, G.; Kalvet, I.; Englert, U.; Schoenebeck, F. J. Am. Chem. Soc.
2015, 137, 4164.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: yhliu@sioc.ac.cn.
ORCID
Yuanhong Liu: 0000-0003-1153-5695
Notes
The authors declare no competing financial interest.
(10) Huang, Y.-J.; Jiang, Y.-B.; Bull, S. D.; Fossey, J. S.; James, T. D.
Chem. Commun. 2009, 46, 8180.
(11) See the Supporting Information for details.
ACKNOWLEDGMENTS
■
(12) Zincate formation between dialkylzinc and n-Bu4NI has been
proposed in Ni-catalyzed coupling reactions of organozinc reagents
with alkyl halides; see: Jensen, A. E.; Knochel, P. J. Org. Chem. 2002,
67, 79.
(13) The use of BHT did not inhibit the reaction. It was assumed
that BHT was not a good radical scavenger under the basic conditions
such as in the presence of DMAP. See: Dawidowicz, A. L.; Olszowy,
M. Eur. Food Res. Technol. 2011, 232, 837. In fact, the proton signal
of the OH group in BHT shifts largely in 1H NMR spectra when BHT
and DMAP are mixed in CD3CN.
(14) (a) Zhao, C.; Jia, X.; Wang, X.; Gong, H. J. Am. Chem. Soc.
2014, 136, 17645. (b) Lamas, M. C.; Vaillard, S. E.; Wibbeling, B.;
Studer, A. Org. Lett. 2010, 12, 2072. (c) Wu, F.; Lu, W.; Qian, Q.;
Ren, Q.; Gong, H. Org. Lett. 2012, 14, 3044.
We thank the National Key Research and Development
Program (2016YFA0202900), the National Natural Science
Foundation of China (21772217), Science and Technology
Commission of Shanghai Municipality (18XD1405000), the
Strategic Priority Research Program of the Chinese Academy
of Sciences (XDB20000000), and the Shanghai Institute of
Organic Chemistry (sioczz201807) for financial support.
REFERENCES
■
(1) Larock, R. C. Comprehensive Organic Transformations: A Guide to
Functional Group Preparations, 2nd ed.; VCH: New York, 1999.
(2) (a) Dhillon, S.; Weber, J. Drugs 2009, 69, 2103. (b) Jones, L. H.;
Summerhill, N. W.; Swain, N. A.; Mills, J. E. MedChemComm 2010, 1,
309. (c) Fleming, F. F.; Yao, L.; Ravikumar, P. C.; Funk, L.; Shook, B.
C. J. Med. Chem. 2010, 53, 7902.
(15) (a) Pezechk, M.; Brunetiere, A. P.; Lallemand, J. Y. Tetrahedron
̈
Lett. 1986, 27, 3715. (b) Hackmann, C.; Schafer, H. J. Tetrahedron
1993, 49, 4559.
(3) For the use of KCN or NaCN as the cyanation reagent, see:
(a) Smiley, R. A.; Arnold, C. J. Org. Chem. 1960, 25, 257. (b) Cook, F.
L.; Bowers, C. W.; Liotta, C. L. J. Org. Chem. 1974, 39, 3416.
(c) Shaw, J. E.; Hsia, D. Y.; Parries, G. S.; Sawyer, T. K. J. Org. Chem.
1978, 43, 1017. (d) Van Driessche, B.; Van Brabandt, W.; D’hooghe,
M.; Dejaegher, Y.; De Kimpe, N. Tetrahedron 2006, 62, 6882. For
cyanation of benzylic halides, see: (e) Brine, G. A.; Boldt, K. G.;
Prakash, D.; Kotchmar, D. J.; Bondeson, V. C.; Bradley, D. J.; Singh,
P.; Carroll, F. I. J. Chem. Soc., Perkin Trans. 1 1991, 1809.
(f) Whitlock, G. A.; Conlon, K.; McMurray, G.; Roberts, L. R.;
Stobie, A.; Thurlow, R. J. Bioorg. Med. Chem. Lett. 2008, 18, 2930.
For the use of TMSCN as the cyanating reagent, see: (g) Zieger, H.
E.; Wo, S. J. Org. Chem. 1994, 59, 3838. (h) Soli, E. D.; Manoso, A. S.;
Patterson, M. C.; DeShong, P.; Favor, D. A.; Hirschmann, R.; Smith,
A. B. J. Org. Chem. 1999, 64, 3171. (i) Griebenow, N.; Flessner, T.;
Buchmueller, A.; Raabe, M.; Bischoff, H.; Kolkhof, P. Bioorg. Med.
Chem. Lett. 2011, 21, 2554.
(4) For a review, see: (a) Anbarasan, P.; Schareina, T.; Beller, M.
Chem. Soc. Rev. 2011, 40, 5049. For selected papers, see the
following. For Pd: (b) Takagi, K.; Okamoto, T.; Sakakibara, Y.; Ohno,
A.; Oka, S.; Hayama, N. Bull. Chem. Soc. Jpn. 1975, 48, 3298. (c) Jin,
F.; Confalone, P. N. Tetrahedron Lett. 2000, 41, 3271. (d) Sunder-
meier, M.; Zapf, A.; Beller, M. Angew. Chem., Int. Ed. 2003, 42, 1661.
(e) Senecal, T. D.; Shu, W.; Buchwald, S. L. Angew. Chem., Int. Ed.
2013, 52, 10035. (f) Cohen, D. T.; Buchwald, S. L. Org. Lett. 2015,
(16) (a) Lu, Z.; Wilsily, A.; Fu, G. C. J. Am. Chem. Soc. 2011, 133,
8154. (b) Zultanski, S. L.; Fu, G. C. J. Am. Chem. Soc. 2011, 133,
15362. (c) Wilsily, A.; Tramutola, F.; Owston, N. A.; Fu, G. C. J. Am.
Chem. Soc. 2012, 134, 5794. (d) Dudnik, A. S.; Fu, G. C. J. Am. Chem.
Soc. 2012, 134, 10693. (e) Binder, J. T.; Cordier, C. J.; Fu, G. C. J.
Am. Chem. Soc. 2012, 134, 17003. (f) Zultanski, S. L.; Fu, G. C. J. Am.
Chem. Soc. 2013, 135, 624. (g) Schley, N. D.; Fu, G. C. J. Am. Chem.
Soc. 2014, 136, 16588. For a mechanistic perspective on nickel-
catalyzed cross-coupling of alkyl electrophiles, see: (h) Hu, X. Chem.
Sci. 2011, 2, 1867.
(17) A 34% yield of 2a was obtained from 1a catalyzed by 5 mol %
of Ni(COD)2/5 mol % of Xantphos/2 equiv of DMAP/0.5 equiv n-
Bu4NCl. Addition of 2 equiv of TEMPO to the above reaction
mixture inhibited the reaction completely. The results indicated that
the reaction might not proceed through a Ni(0)/Ni(II) pathway. See
the Supporting Information.
(18) Jones, G. D.; Martin, J. L.; McFarland, C.; Allen, O. R.; Hall, R.
E.; Haley, A. D.; Brandon, R. J.; Konovalova, T.; Desrochers, P. J.;
Pulay, P.; Vicic, D. A. J. Am. Chem. Soc. 2006, 128, 13175.
̀
17, 202 For Ni: . (g) Cassar, L.; Foa, M.; Montanari, F.; Marinelli, G.
P. J. Organomet. Chem. 1979, 173, 335. (h) Sakakibara, Y.; Okuda, F.;
Shimobayashi, A.; Kirino, K.; Sakai, M.; Uchino, N.; Takagi, K. Bull.
Chem. Soc. Jpn. 1988, 61, 1985. (i) Sakakibara, Y.; Ido, Y.; Sasaki, K.;
Sakai, M.; Uchino, N. Bull. Chem. Soc. Jpn. 1993, 66, 2776.
(j) Sakakibara, Y.; Sasaki, K.; Okuda, F.; Hokimoto, A.; Ueda, T.;
Sakai, M.; Takagi, K. Bull. Chem. Soc. Jpn. 2004, 77, 1013. For our
recent work: (k) Zhang, X.; Xia, A.; Chen, H.; Liu, Y. Org. Lett. 2017,
19, 2118. For a more recent work using butyronitrile as the cyanating
reagent: (l) Yu, P.; Morandi, B. Angew. Chem., Int. Ed. 2017, 56,
15693.
(5) (a) Frisch, A. C.; Beller, M. Angew. Chem., Int. Ed. 2005, 44, 674.
(b) Rudolph, A.; Lautens, M. Angew. Chem., Int. Ed. 2009, 48, 2656.
(6) (a) Ren, Y.; Yan, M.; Zhao, S.; Sun, Y.; Wang, J.; Yin, W.; Liu, Z.
Tetrahedron Lett. 2011, 52, 5107. (b) Ren, Y.; Dong, C.; Zhao, S.;
E
DOI: 10.1021/acs.orglett.8b03539
Org. Lett. XXXX, XXX, XXX−XXX