Copper-Catalyzed Tertiary Alkylative Cyanation for the Synthesis of Cyanated Peptide Building Blocks

Article abstract of DOI:10.1021/jacs.9b11349

In this paper, we report efficient cyanation of various peptides containing the α-bromocarbonyl moiety using a Cu-catalyzed radical-based methodology employing zinc cyanide as the cyanide source. Mechanistic studies revealed that in situ formed CuCN was a key intermediate during the catalytic cycle. Our method could be useful for the synthesis of modified peptides containing quaternary carbons.

Full text of DOI:10.1021/jacs.9b11349

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Copper-Catalyzed Tertiary Alkylative Cyanation for the Synthesis of
Cyanated Peptide Building Blocks
Naoki Miwa, Chihiro Tanaka, Syo Ishida, Goki Hirata, Jizhou Song, Takeru Torigoe,
Yoichiro Kuninobu,* and Takashi Nishikata*
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ABSTRACT: In this paper, we report efficient cyanation of various peptides containing the α-bromocarbonyl moiety using a Cu-
catalyzed radical-based methodology employing zinc cyanide as the cyanide source. Mechanistic studies revealed that in situ formed
CuCN was a key intermediate during the catalytic cycle. Our method could be useful for the synthesis of modified peptides
containing quaternary carbons.
he modification of peptides, including those containing
natural and unnatural amino acid moieties, is essential for
isocyanation.7 Recent progress in this area includes the use of a
photoredox system to produce nonfunctionalized alkyl
cyanide,8 boron enolate to provide α-ketocyanide,9 and
enantioselective benzylic C−H cyanation to obtain sec-alkyl
cyanide.10 Additionally, issues with cyanation at the tertiary
carbon atom include the following: (1) low yield, (2)
chemoselectivity, (3) functional group compatibilities, and
(4) α-cyanation of carboxamides for modification of peptides.
Recently, we demonstrated the coupling of fluoride, amine,
and alkyne with α-bromocarboxamides containing a tert-alkyl
structure.11 In these reactions, copper fluoride, copper amide,
and alkynyl copper were key intermediates. Based on these
findings, we hypothesized that α-bromocarboxamide could
react with copper cyanide, generated in situ (Scheme 2). α-
T
protein chemistry.1,2 Thus, overcoming the challenges to
incorporate various functional groups into peptides contributes
to not only the new synthetic methodology but also protein
chemistry. In this context, cyanation of peptides is a key
strategy because the cyano group can be easily converted to
amine, aldehyde, ketone, and carboxylic acid groups. However,
cyanation reaction on peptide derivatives could be limited by
incompatible functional groups on the peptides and steric
issues, since the reaction needs to occur at a tertiary carbon
atom.
Cyanide, a small but reactive nucleophile, is useful to carry
out a substitution reaction (SN2) with primary and secondary
alkyl halides.3 Although the formation of a Csp2−CN bond by a
transition metal catalyst has been well investigated (Scheme
1a),4,5 the reaction of a tertiary-alkyl halide with cyanide is still
Scheme 2. This work
Scheme 1. Cyanation Reactions and Their Limitations
Bromocarbonyl compounds are useful building blocks as a
quaternary carbon precursor, but they cannot react with a
cyanide via the SN1 or SN2 mechanism. Herein, we show the
coupling reaction of α-bromocarboxamides and their peptide
derivatives with zinc cyanide in the presence of a copper
catalyst. The advantages of this methodology are that it uses
Zn(CN)2, a stable and safe cyanide source, and it allows
unexplored (Scheme 1b). In 1981, Reetz and co-workers
reported an SN1 reaction of tert-alkyl halides and TMSCN
(Me3SiCN) in the presence of SnCl4 as a strong Lewis acid.6
However, they had used only nonfunctionalized and specific
alkyl groups due to poor compatibility with functional groups.
Moreover, the reported yields were low to moderate.
Furthermore, cyanation via SN1 reaction has the risk of
Received: October 22, 2019
https://dx.doi.org/10.1021/jacs.9b11349
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© XXXX American Chemical Society
A

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Table 1. Ligand Effect
Ligands
none: 11%
PPh3: 33%
2,2′-bpy: 23%
N(CH22-Py)3 (TPMA): 9%
MeN(CH2CH2NMe2)2 (PMDETA): 44%
b
c
(CH2NMe2)2 (TMEDA): 81% (93%, 88% )
a
All reactions were conducted with 1 (1.0 equiv), Zn(CN)2 (2: 1.0 equiv), CuBr·SMe2 (10 mol %), ligand (30 mol %), K3PO4 (1.5 equiv), in 1,4-
b
c
1
dioxane for 24 h at 110 °C. Yields were determined by H NMR analysis. THF was used instead of 1,4-dioxane in a sealed tube. 1.5 equiv of
Zn(CN)2 was used.
a
incorporation of an unnatural β-amino acid moiety into
oligopeptides.
Table 2. Substrate Scope
Initially, we screened various candidates as the CN source,
such as Zn(CN)2(2), TMSCN,12 cyanohydrins, and iron
cyanides for the reaction of α-bromocarboxamide (1a), and
found Zn(CN)2 (2) to be a good CN source, in the presence
of a copper catalyst. In Cu-catalyzed reactions, the use of
Zn(CN)2(2), even in reactions involving sp2 hybridized carbon
(Csp2-CN), is limited by its poor solubilitty.13 We also tried
the reaction with the stoichiometric amounts of CuCN, which
is known as a source of Lipshutz’s reagent (CN as a dummy
group);14 however, the yield of 3a was low and Lewis acidic
CuCN caused the hydration of CN (discussed later, see
Scheme 6II). In this reaction, both a ligand and a base need to
undergo the cyanation reaction (see SI: Table S1). The
accurate role of base was not clear at this stage, but K3PO4
showed high reactivity. Other bases mainly produced
acrylamide, which is the elimination product of 1. The
reaction without a ligand gave an 11% yield of 3a. Phosphorus
and nitrogen ligands were screened, and TMEDA resulted in
the highest yield of 3a. Increasing the amount of 2 was
ineffective; however, using THF instead of 1,4-dioxane
produced the best yield. In previous studies, we showed that
multidentate nitrogen ligands, such as TPMA and PMDETA,
generate alkyl radicals from α-bromocarbonyls.11,15 Therefore,
we expected that multidentate nitrogen ligands could be
effective in this reaction. However, TMEDA, a bidentate
ligand, was found to be the most effective ligand (Table 1 and
Scheme 3). The reactivity of Zn(CN)2 was low for 1a in the
Scheme 3. Cyanation of α-Bromocarboxamide 4a
a
See SI. Isolated product yields are reported. Yields shown in
b
parentheses were determined by 1H NMR analysis. Isolated yields by
GPC.
3b−3f. For example, 1f possessing long alkyl chains at the α-
position of carbonyl group resulted in a 71% yield of 3f.
However, cyclic bromides (1g−1h) resulted in moderate yields
of 3g−3h because of preferential HBr eliminations from 1 to
give methacrylamide derivatives. Transition metal cyanide
showed various reactivities,5,16 but our cyanation reaction
provided good functional group compatibility (3j−3r).
Although ArI reacts with cyanide under copper-catalyzed
conditions,5,16 Ar−I bonds remained intact (3m and 3r). On
the other hand, borylated 1n did not show good reactivity; the
carbon−boron bond cleavage was detected. In this reaction,
free cyanide might not be generated. When 1o−1q possessing
alkyl-Br bonds were employed for the cyanation, no SN2
reactions at alkyl-Br bonds with cyanide were observed. The
absence of a catalyst. Therefore, Cu catalyst was necessary to
carry out the cyanation reaction. We expected that the current
cyanation reaction could involve a radical species, but
considering the ligand effect, the reaction cannot be a simple
radical reaction. A cation reaction, SN1, was one of the
possibilities, but the isonitrile product, which would be
generated from the reaction of a carbocation and cyanide,
was not obtained.
The reactivities of various α-bromocarboxamides (1) were
examined under the optimized reaction conditions (Table 2).
Sterically hindered bromides (1b−1f) showed good yields of
B
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yields of 3o−3q were moderate to good because of HBr
elimination of 1. Other combinations using 1s and 1t resulted
in 74% and 71% isolated yields of 3s and 3t, respectively. The
NMR yields of 3 were good, but isolated yields were moderate
to good because the purification was sometimes difficult due to
inseparable side products such as products of reduction and
H−Br elimination of 1. The substituents on amide is necessary
to carry out our cyanation reaction. Cyanation at a primary- or
secondary-carbon atom is well-established, but we were not
able to detect any cyanations with α-bromocarbonyls
possessing a primary- or secondary-carbon atom. Under our
conditions, primary- and secondary-alkyl radical species could
not be generated and the starting materials partly remained or
decomposed. Next, we examined the cyanation reaction with
α-bromocarboxamide 4a (monopeptide) (Scheme 3), but the
reactivity was not good under optimized conditions (Con-
ditions A in Table 1). We speculated that this result was
attributed to strong ligation (chelation) of 4a to copper, which
might have decreased the catalytic activity of the copper salt.
Avoidance of catalyst poisoning could be challenging during
cyanation of peptides containing an α-bromocarboxamide. For
this, we screened various additives and ligands. Zinc additives
and the PPh3 ligand were suitable for the cyanation of 4a with
a peptide moiety. The yield of 5a was improved (see SI: Table
S2). We speculate that Zn might bind to peptides to replace
Cu allowing recovery of its activity. Sterically hindered and
highly functionalized peptides are not considered to be ideal
substrates, especially for transition-metal-catalyzed cyanation
reaction because cyanide is also a catalyst poison for copper
and other metal catalysts. Thus, these results could provide the
next generation cyanation protocol.
around 50% to 60% yield of 5d−5g, 5j−5m, 5o, and 5p,
respectively. We did not observe epimerization of chiral amino
acid units in 5p. Reactions of highly sterically congested and
functionalized peptide 4b, 4c, 4h, and 4n did not show good
reactivities. Peptide-containing free carboxylic acid 4i was
sluggish.
Our cyanation reaction is useful to synthesize functionalized
building blocks because the CN group can easily access various
functional groups such as amine and carboxylic acid. We
demonstrated four chemical transformations of 3a in Scheme 4
a
Scheme 4. Transformation of CN Group
a
Isolated yields are reported.
as examples. The reaction of 3a in the presence of LiAlH4
(LAH) resulted in the formation of a diamine 6 in 85% yield.
The reaction of 3a and stoichiometric amounts of CuCN
produced the corresponding amide compound in 53% yield.
Hydrolysis of CN group to give 8 was easy in the presence of
H2O2. The reduction of 3a in the presence of Co salt and
NaBH4 resulted in 9, which contained a β-amino group, in
80% yield.
Recently, peptides with natural α-amino acid moieties have
been synthesized by using active aminocarbonyl or amino-
nitrile derivatives2,17,18 or a special catalyst system.19 The
current cyanation methodology provides a synthetic route for a
modified peptide that has a β-amino acid moiety incorporated
within it. The cyanation of 10 possessing dipeptide fragment
gave a 42% yield of 11 (Scheme 5). After Co-mediated
Using optimized conditions (Conditions B in Scheme 3),
various peptides possessing an α-bromocarboxamide were
cyanated (4b−4p) (Table 3). In this study, isolations were
difficult due to generation of side products (elimination and
reduction of 4). Therefore, NMR yields were higher than
isolation yields. Although catalyst poisoning was high in the
reactions with peptide derivatives 4, yields were mostly
reasonable. For example, 4d−4g, 4j−4m, 4o, and 4p gave
Table 3. Cyanations of Peptide with an α-
a
Bromocarboxamide
Scheme 5. Synthesis of Modified Peptide Having α-Amino
a
Acid
a
Isolated yields are reported.
reduction of 12, the modified peptide 13 having a β-amino
acid moiety was obtained in 36% yield. The chemical yield of
13 was not high probably because 13 might be decomposed
during aqueous workup.
An outline for plausible copper-catalyzed cyanation mech-
anisms is shown in Figure 1. The reaction of CuX and
Zn(CN)2 could give copper cyanide (A). The resulting A
could react with 1 to generate 3 via a transient intermediate
a
See SI. Isolated product yields are reported. Yields shown in
1
parentheses were determined by H NMR analysis.
C
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concomitant formation of hydrolyzed product 7 in 31% yield.
The Lewis acidity of CuCN15 could accelerate the reaction of
3 and K3PO4 to generate 7 (Scheme 4). This is the reason why
stoichiometric CuCN was not a good CN source compared
with Zn(CN)2. We also tried the reaction in the absence of
K3PO4, but no product was obtained. In the absence of
TMEDA, a 43% yield of 3a was obtained. Thus, TMEDA plays
an important role in the formation of 7 because the reaction
without TMEDA did not give 7. Based on these observations,
three possible pathways for the C−CN formation step could be
considered (Figure 1 bottom).
Path (i): B could be generated via deprotonation of NH
followed by the ligation of CuCN. Compound 3 could be
generated via an intramolecular substitution reaction. Path (ii):
B′ could be obtained via intramolecular single electron transfer
of B. B′ could undergo a radical addition to CN followed by
elimination to produce 3. Path (iii): B′′ could be obtained via
migratory insertion of B′. Next B′′ could undergo reductive
elimination to produce 3. We tried to detect each intermediate
but failed. For example, the reaction of 1a and copper salt in
the presence of K3PO4 did not yield any metal complex (1a
was recovered completely). Although we have no direct proof
of the existence of a radical species, the cyanation reaction was
moderately inhibited by the addition of BHT or TEMPO,
which indicated the involvement of a short-lifetime radical
species (Scheme 6III). Finally, we used CuCN (A) as a catalyst
in the reaction of 1a and 2 under the optimized conditions. As
a result, 3a was obtained in 80% yield (Scheme 6IV). This
result indicated that CuCN (A) could be the key intermediate
in the catalytic cycle.
Figure 1. Possible mechanism
a
Scheme 6. Control Experiments
In summary, we successfully demonstrated Cu-catalyzed
cyanation of α-bromocarboxamides and their peptide deriva-
tives in the presence of zinc cyanide. Cyanation at a highly
congested and functionalized reaction site was found to be
difficult; however, the Cu catalyst system enabled efficient
cyanation via CuCN which is formed by a transmetalation
reaction between CuBr and zinc cyanide.
ASSOCIATED CONTENT
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* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/jacs.9b11349.
Screening data, experimental details, characterization of
new compounds, and NMR spectra (PDF)
AUTHOR INFORMATION
■
a
Isolated yields are reported.
Corresponding Authors
Yoichiro Kuninobu − Kyushu University, Kasuga, Japan;
orcid.org/0000-0002-8679-9487;
Email: kuninobu@cm.kyushu-u.ac.jp
Takashi Nishikata − Yamaguchi University, Ube, Japan;
orcid.org/0000-0002-6104-7684; Email: nisikata@
yamaguchi-u.ac.jp
(B, B′, or B′′). Although the overall reaction mechanism is still
unclear, we conducted control experiments to support our
postulated mechanism (Scheme 6). The transmetalation
between CuX and Zn(CN)2 is known, and the resulting
product should be CuCN or a multinuclear metal complex.20
IR studies revealed the generation of CuCN from the reaction
of 2 and CuBr·SMe2. The mixture of CuCN and TMEDA
showed a CN peak at 2108 cm−1. A similar peak (2113 cm−1)
was observed when 2 was reacted with CuBr·SMe2 (Scheme
6I). Next, the reactivity of CuCN (A) was checked (Scheme
6II). When the reaction of CuCN (A) and 1a was carried out
in the presence/absence of K3PO4 and TMEDA, the
corresponding product 3a was obtained in 26% yield with
Other Authors
Naoki Miwa − Yamaguchi University, Ube, Japan
Chihiro Tanaka − Yamaguchi University, Ube, Japan
Syo Ishida − Yamaguchi University, Ube, Japan
Goki Hirata − Yamaguchi University, Ube, Japan
Jizhou Song − Kyushu University, Kasuga, Japan
D
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Chem., Int. Ed. 2012, 51, 11948−11959. (c) Anbarasan, P.; Schareina,
T.; Beller, M. Recent developments and perspectives in palladium-
catalyzed cyanation of aryl halides: synthesis of benzonitriles. Chem.
Soc. Rev. 2011, 40, 5049−5067.
Takeru Torigoe − Kyushu University, Kasuga, Japan;
orcid.org/0000-0002-4902-1596
Complete contact information is available at:
https://pubs.acs.org/10.1021/jacs.9b11349
(6) (a) Ellis, G. P.; Romney-Alexander, T. M. Cyanation of aromatic
halides. Chem. Rev. 1987, 87, 779−794. (b) Reetz, M. T.;
Chatziiosifidis, I.; Kunzer, H.; Muller-Starke, H. Trimethylsilyl
̈ ̈
Notes
cyanide promoted cyanation of tertiary alkyl chlorides and other
SN1 active compounds. Tetrahedron 1983, 39, 961−965. (c) Reetz, M.
T.; Chatziiosifidis, I. Cyanation of Tertiary Alkyl Chlorides: A Novel
Method for the Geminal Dialkylation of Ketones. Angew. Chem., Int.
Ed. Engl. 1981, 20, 1017−1018.
(7) (a) Yurino, T.; Tani, R.; Ohkuma, T. Pd-Catalyzed Allylic
Isocyanation: Nucleophilic N-Terminus Substitution of Ambident
Cyanide. ACS Catal. 2019, 9, 4434−4440. (b) Tishkov, A. A.; Mayr,
H. Ambident Reactivity of the Cyanide Ion: A Failure of the HSAB
Principle. Angew. Chem., Int. Ed. 2005, 44, 142−145. (c) Sasaki, T.;
Nakanishi, A.; Ohno, M. Synthesis of adamantane derivatives. 56.
Reaction of 1-adamantyl chloride with trimethylsilyl pseudohalide. J.
Org. Chem. 1981, 46, 5445−5447. (d) Songstad, J.; Stangeland, L. J.;
Austad, T. Isonitriles from Alkyl Halides and Onium Dicyanoargen-
tates. Acta Chem. Scand. 1970, 24, 355−356.
(8) Ratani, T. S.; Bachman, S.; Fu, G. C.; Peters, J. C. Photoinduced,
Copper-Catalyzed Carbon-Carbon Bond Formation with Alkyl
Electrophiles: Cyanation of Unactivated Secondary Alkyl Chlorides
at Room Temperature. J. Am. Chem. Soc. 2015, 137, 13902−13907.
(9) Kiyokawa, K.; Nagata, T.; Minakata, S. Electrophilic Cyanation
of Boron Enolates: Efficient Access to Various β-Ketonitrile
Derivatives. Angew. Chem., Int. Ed. 2016, 55, 10458−10462.
(10) Zhang, W.; Wang, F.; McCann, S. D.; Wang, D.; Chen, P.;
Stahl, S. S.; Liu, G. Enantioselective cyanation of benzylic C-H bonds
via copper-catalyzed radical relay. Science 2016, 353, 1014−1018.
(11) (a) Yamane, Y.; Miwa, N.; Nishikata, T. Copper-Catalyzed
Functionalized Tertiary-Alkylative Sonogashira Type Couplings via
Copper Acetylide at Room Temperature. ACS Catal. 2017, 7, 6872−
6876. (b) Ishida, S.; Takeuchi, K.; Taniyama, N.; Sunada, Y.;
Nishikata, T. Copper-Catalyzed Amination of Congested and
Functionalized α-Bromocarboxamides with either Amines or
Ammonia at Room Temperature. Angew. Chem., Int. Ed. 2017, 56,
11610−11614. (c) Nishikata, T.; Ishida, S.; Fujimoto, R. Site-
Selective Tertiary Alkyl-Fluorine Bond Formation from α-Bromoa-
mides Using a Copper/CsF Catalyst System. Angew. Chem., Int. Ed.
2016, 55, 10008−10012.
(12) (a) Kurono, N.; Arai, K.; Uemura, M.; Ohkuma, T.
[Ru(phgly)2(binap)]/Li2CO3: A Highly Active, Robust, and
Enantioselective Catalyst for the Cyanosilylation of Aldehydes.
Angew. Chem., Int. Ed. 2008, 47, 6643−6646. (b) Takamura, M.;
Funabashi, K.; Kanai, M.; Shibasaki, M. Asymmetric Reissert-type
Reaction Promoted by Bifunctional Catalyst. J. Am. Chem. Soc. 2000,
122, 6327−6328.
(13) (a) Zhang, X.; Xie, X.; Liu, Y. Nickel-Catalyzed Highly
Regioselective Hydrocyanation of Terminal Alkynes with Zn-
(CN)2Using Water as the Hydrogen Source. J. Am. Chem. Soc.
2018, 140, 7385−7389. (b) Zhang, X.; Xia, A.; Chen, H.; Liu, Y.
General and Mild Nickel-Catalyzed Cyanation of Aryl/Heteroaryl
Chlorides with Zn(CN)2: Key Roles of DMAP. Org. Lett. 2017, 19,
2118−2121. (c) Tschaen, D. M.; Desmond, R.; King, A. O.; Fortin,
M. C.; Pipik, B.; King, S.; Verhoeven, T. R. An Improved Procedure
for Aromatic Cyanation. Synth. Commun. 1994, 24, 887−890.
(14) ((a) )Krause, N., Ed. Modern Organocopper Chemistry; Wiley-
VCH: 2002. (b) Lipshutz, B. H.; Elsworth, E. L.; Siahaan, T. The role
of boron trifluoride etherate in reactions of lower order (Gilman)
organocuprates. J. Am. Chem. Soc. 1989, 111, 1351−1358.
(c) Lipshutz, B. H.; Wilhelm, R. S.; Floyd, D. M. Chemistry of
higher order, mixed organocuprates. 1. Substitution reactions at
unactivated secondary centers. J. Am. Chem. Soc. 1981, 103, 7672−
7674.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We warmly thank Yamaguchi University (T.N.), the Naito
Foundation, JSPS KAKENHI for Grant Numbers JP18H04654
and 18H04656 in Hybrid Catalysis for Enabling Molecular
Synthesis on Demand (T.N. and Y.K.), and JSPS KAKENHI
for Grant Number 18K19182 in Challenging Research
(Exploratory) (T.N.).
REFERENCES
■
(1) (a) Alam, J.; Keller, T. H.; Loh, T.-P. Functionalization of
Peptides and Proteins by Mukaiyama Aldol Reaction. J. Am. Chem.
Soc. 2010, 132, 9546−9548. (b) Sletten, E. M.; Bertozzi, C. R.
Bioorthogonal Chemistry: Fishing for Selectivity in a Sea of
Functionality. Angew. Chem., Int. Ed. 2009, 48, 6974−6998.
(c) Wang, L.; Schultz, P. G. Expanding the Genetic Code. Angew.
Chem., Int. Ed. 2005, 44, 34−66. (d) Link, A. J.; Mock, M. L.; Tirrell,
D. A. Non-canonical amino acids in protein engineering. Curr. Opin.
Biotechnol. 2003, 14, 603−609. (e) Melnyk, O.; Fehrentz, J.-A.;
Martinez, J.; Gras-Masse, H. Functionalization of peptides and
proteins by aldehyde or keto groups. Biopolymers 2000, 55, 165−186.
(2) (a) Canavelli, P.; Islam, S.; Powner, M. Peptide ligation by
chemoselective aminonitrile coupling in water. Nature 2019, 571,
546−549. (b) Bode, J. W. Chemical Protein Synthesis with the α-
Ketoacid-Hydroxylamine Ligation. Acc. Chem. Res. 2017, 50, 2104−
2115. (c) Taguchi, J.; Ikeda, T.; Takahashi, R.; Sasaki, I.; Ogasawara,
Y.; Dairi, T.; Kato, N.; Yamamoto, Y.; Bode, J. W.; Ito, H. Synthesis of
Acylborons by Ozonolysis of Alkenylboronates: Preparation of an
Enantioenriched Amino Acid Acylboronate. Angew. Chem., Int. Ed.
2017, 56, 13847−13851. (d) Dumas, A. M.; Molander, G. A.; Bode, J.
W. Amide-Forming Ligation of Acyltrifluoroborates and Hydroxyl-
amines in Water. Angew. Chem., Int. Ed. 2012, 51, 5683−5686.
(e) Carrillo, N.; Davalos, E. A.; Russak, J. A.; Bode, J. W. Iterative,
Aqueous Synthesis of β3-Oligopeptides without Coupling Reagents. J.
Am. Chem. Soc. 2006, 128, 1452−1453.
(3) Rappoport, Z., Patai, S., Eds. The Chemistry of the Cyano group;
Wiley: New York, 1970.
(4) (a) Satoh, Y.; Obora, Y. Synthesis of arylacetonitrile derivatives:
Ni-catalyzed reaction of benzyl chlorides with trimethylsilyl cyanide
under base-free conditions. RSC Adv. 2014, 4, 15736−15739.
(b) Ren, Y.; Dong, C.; Zhao, S.; Sun, Y.; Wang, J.; Ma, J.; Hou, C.
Copper-catalyzed cyanation of benzyl chlorides with non-toxic
K4[Fe(CN)6]. Tetrahedron Lett. 2012, 53, 2825−2827. (c) Ren, Y.;
Yan, M.; Zhao, S.; Sun, Y.; Wang, J.; Yin, W.; Liu, Z. Pd-catalyzed
cyanation of benzyl chlorides with nontoxic K4[Fe(CN)6]. Tetrahe-
dron Lett. 2011, 52, 5107−5109. (d) Shaw, J. E.; Hsia, D. Y.; Parries,
G. S.; Sawyer, T. K. Reaction of alkali metal cyanides with alkyl
halides in HMPA or HMPA containing crown ether. J. Org. Chem.
1978, 43, 1017−1018. (e) Cook, F. L.; Bowers, C. W.; Liotta, C. L.
Chemistry of naked anions. III. Reactions of the 18-crown-6 complex
of potassium cyanide with organic substrates in aprotic organic
solvents. J. Org. Chem. 1974, 39, 3416−3418. (f) Starks, C. M.;
Owens, R. M. Phase-transfer catalysis. II. Kinetic details of cyanide
displacement on 1-halooctanes. J. Am. Chem. Soc. 1973, 95, 3613−
3617. (g) Smiley, R. A.; Arnold, C. Notes- Aliphatic Nitriles from
Alkyl Chlorides. J. Org. Chem. 1960, 25, 257−258.
(5) See reviews: (a) Wen, Q.; Jin, J.; Zhang, L.; Luo, Y.; Lu, P.;
Wang, Y. Copper-mediated cyanation reactions. Tetrahedron Lett.
2014, 55, 1271−1280. (b) Kim, J.; Kim, H. J.; Chang, S. Synthesis of
aromatic nitriles using nonmetallic cyano-group sources. Angew.
(15) The effect of nitrogen ligands: (a) Eckenhoff, W. T.; Pintauer,
T. Atom transfer radical addition (ATRA) catalyzed by copper
E
https://dx.doi.org/10.1021/jacs.9b11349
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
pubs.acs.org/JACS
Communication
complexes withtris[2-(dimethylamino)ethyl]amine(Me6TREN) ligan-
din the presence of free-radical diazo initiator AIBN. Dalton Trans.
2011, 40, 4909−4917. (b) Taylor, M. J. W.; Eckenhoff, W. T.;
Pintauer, T. Copper-catalyzed atom transfer radical addition (ATRA)
and cyclization (ATRC) reactions in the presence of environmentally
bening ascorbic acid fas a reducing agent. Dalton Trans. 2010, 39,
11475−11482.
(16) (a) Jiang, Z.; Huang, Q.; Chen, S.; Long, L.; Zhou, X. Copper-
Catalyzed Cyanation of Aryl Iodides with Malononitrile: An Unusual
Cyano Group Transfer Process from C(sp3) to C(sp2). Adv. Synth.
́
Catal. 2012, 354, 589−592. (b) Schareina, T.; Zapf, A.; Cotte, A.;
Gotta, M.; Beller, M. A Versatile Protocol for Copper-Catalyzed
Cyanation of Aryl and Heteroaryl Bromides with Acetone
Cyanohydrin. Adv. Synth. Catal. 2011, 353, 777−780.
(17) Bode, J. W.; Fox, R. M.; Baucom, K. D. Chemoselective Amide
Ligations by Decarboxylative Condensations of N-Alkylhydroxyl-
amines and α-Ketoacids. Angew. Chem., Int. Ed. 2006, 45, 1248−1252.
(18) Harmand, T. J. R.; Murar, C. E.; Bode, J. W. New chemistries
for chemoselective peptide ligations and the total synthesis of
proteins. Curr. Opin. Chem. Biol. 2014, 22, 115−121.
(19) Muramatsu, W.; Hattori, T.; Yamamoto, H. Substrate-Directed
Lewis-Acid Catalysis for Peptide Synthesis. J. Am. Chem. Soc. 2019,
141, 12288−12295.
(20) Ouyang, L.; Aguiar, P. M.; Batchelor, R. J.; Kroeker, S.; Leznoff,
D. B. A paramagnetic Cu(I)/Cu(II)/Zn(II) coordination polymer
with multiple CN-binding modes and its solid-state NMR character-
ization. Chem. Commun. 2006, 744−746.
F
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