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Ni-Mediated Generation of “CN“ Unit from Formamide and Its Catalysis in the Cyanation Reactions Luo Yang, Yu-Ting Liu, Yoonsu Park, Sung-Woo Park, and Sukbok Chang ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.8b05111 • Publication Date (Web): 14 Mar 2019 Downloaded from http://pubs.acs.org on March 14, 2019
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ACS Catalysis
Ni-Mediated Generation of “CN“ Unit from Formamide and Its Catalysis in the Cyanation Reactions Luo Yang,†,* Yu-Ting Liu,† Yoonsu Park,‡,§ Sung-Woo Park,§,‡ and Sukbok Chang§,‡,* †Key
Laboratory for Green Organic Synthesis and Application of Hunan Province, College of Chemistry, Xiangtan University, Hunan 411105, PR China ‡Department
of Chemistry, Korea Advanced Institute of Science & Technology (KAIST), Daejeon 34141, Republic of
Korea §Center
for Catalytic Hydrocarbon Functionalizations, Institute for Basic Science (IBS), Daejeon 34141, Republic of
Korea KEYWORDS: cyano source, formamide, Ni catalyst, hydrocyanation, alkynes, aryl halides
ABSTRACT: The in situ generation of a “cyano” unit from readily available organic precursors is of high interest in synthetic chemistry. Herein we report the first example of Ni-mediated dehydration of formamide to form “CN” and its subsequent catalytic applications in the hydrocyanation of alkynes and cyanation of aryl halides. Formamide can serve as a convenient source for the nitrile unit in that it releases water as the only by-product. HCONH2 [Ni] H
[Ni/Co]
R CN R
R
"CN" R
[Ni/Al] Ar X
Ar CN
(X: Br, I)
Formamide as a convenient cyano source Ni-mediated dehydration of formamide to genertae "CN" Applied in the hydrocyantion of alkynes and cyanation of aryl bromides
Nitrile constitutes a prevalent unit in numerous natural products, pharmaceuticals, and agrochemicals.1 It also serves as a versatile precursor to a range of synthetic functional groups such as amines, amides, aldehydes, amidines, ketones, and carboxylic acids.2 Therefore, a handful of preparative procedures of introducing the nitrile group onto organic compounds has been developed by employing various cyano sources. Aryl nitriles can readily be obtained by classical methods, such as the Sandmeyer reaction or the Rosenmund-von Braun protocol using copper(I) cyanide.3 Coupling partners frequently employed in the transition metal-catalyzed cyanation reactions are metal- or metalloid cyanides such as KCN, NaCN, Zn(CN)2, TMSCN or K4[Fe(CN)6] (Scheme 1A).4 An another array of organic cyano precursors that do not contain metal elements has been scrutinized in recent years. Representative examples include cyanohydrin, Ncyanosuccinimide, N-cyano-p-toluenesulfonamide, Ncyanoimindazole, aryl(cyano)iodonium, cyanogen
bromide, and acetonitrile (Scheme 1B).5 Isovaleronitrile has also been proved to be a versatile “CN” source in a reversible transfer hydrocyanation of alkenes.6 While each approach bears its own merits, most procedures have intrinsic drawbacks in that the cyano sources are often toxic and/or produce stoichiometric byproducts. In addition, a careful control of cyanide concentration is often required to obtain satisfactory catalytic reactivity.7 An alternative approach is to generate the cyano group in situ from readily available non-toxic organic precursors. One of the authors previously developed a procedure of generating “CN” from “combined” cyano precursors mediated by Cu or Pd catalyst systems.8 In this protocol, a combination of two compounds was employed to generate cyano under oxidative conditions. For instance, dimethylformamide and ammonia or its halide salts were found to work cooperatively to serve carbon and nitrogen of the “CN”, respectively (Scheme 1C, left). This approach was successfully utilized in the chelation-assisted CH
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cyanation of arenes and indoles as well as in the cyanation of aryl boronic acids and aryl halides.9 Subsequently, Cheng, Yu, Sakai, and Jiao groups independently showed that an additional array of organic compounds can also serve as cyano precursors, including DMSO, TMEDA, nitromethane, or sodium azide.10a-i Bhanage and coworkers reported a Pd-catalyzed cyanation of aryl iodides with formamide as the cyano source in the presence of POCl3, wherein an Ar-Pd intermediate was proposed to insert into the C=N bond of a Vilsmer intermediate generated from a reaction of formamide with POCl3.10j-k Herein, we report the first example of in situ generation of “CN” unit from formamide via nickel catalysis (Scheme 1C, right). This precursor is especially noteworthy as a cyano source in that it generates water as a single byproduct. This new procedure was further leveraged to catalyze hydrocyanation of alkynes and cyanation of aryl halides.
observed a color change from yellow to red in a picrate impregnated indicator paper, which implied the formation of cyanide anion.9b,10c At the same time, reductive formation of ammonium formate was also monitored by 13C NMR, which would be generated from a reaction of formamide with water that is produced from the formamide dehydration.12 DFT calculations of the putative pathway suggested that HCN generation, indeed, is facilitated by the coordination of formamide to the ligated nickel metal center (Scheme 3). Upon binding of formamide to the metal center, deprotonation of an amide moiety by acetylacetonate base becomes thermodynamically accessible (I to II), and a reasonable kinetic barrier for this dehydration process was also calculated (31.9 kcal/mol, II to III-TS).
2
A. Cyanation with metal- or metalloid-"CN" sources +
Ar X
cat. Pd, Ni, or Cu
MCN
X = N2 , I, Br, Cl, OTf MCN = CuCN, KCN, NaCN, Zn(CN)2, TMSCN, K4[Fe(CN)6] etc.
cat. Pd, Ni, or Cu
R-CN
Ni(acac)2 (0.01 mmol) bpy (0.06 mmol) NH2
145 oC, 12 h
H O
N H C N Ni N
Ar CN
X = H, B(OH)2, I, Br R-CN =
OH CN ,
III-TS
O N CN ,
HCN + HCO2- NH4+
detected by detected by picrate paper 13C NMR
G (kcal/mol)
B. Cyanation with organic "CN" sources +
H
O C
Scheme 2. Proof of principle: generation of HCN at mild temperature. The color of picrate impregnated indicator paper changed from yellow (left, blank) to red (right, after absorbing HCN.). bpy, 2,2’-bipyridine.
Ar CN
+
Ar X
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Ts
CN N N Ph,
N CN ,
Br-CN ,
I (0.0)
CH3-CN
acac
O
C. Cyanation with organic precursors (our contributions) "CN" from two C and N sources cat. CHO [Pd] or [Cu] H 3C N + NH3 [O] CH3
O 2+ N H C Ni N H N H I
"CN" from formamide "CN"
cat. [Ni] H
O C
NH2 H C
current study
O
+
Ni
N
N N H II
Scheme 1. Cyanation with various “CN” sources.
III-TS (-32.58)
III (-36.49)
acacH 31.93 kcal/mol IV (-48.11)
II (-64.51) H C
H O N
+
Ni
III
HO
N
N
H
C
N
+
Ni
N
N
IV
Scheme 3. Potential energy profile for HCN formation
Dehydration of formamide to hydrocyanic acid was previously known to proceed at high temperatures in the range of ~500 oC.11 We were curious to see whether the same transformation would be facilitated by transition metal catalysts, and, moreover, the in situ generated “CN” unit could be subsequently incorporated into organic compounds eventually to make nitrile products. Based on this initial working hypothesis, we screened a series of late transition metal-based catalytic conditions, and discovered that a nickel catalyst system is capable of generating hydrocyanic acid at lower temperature (Scheme 2). Upon heating formamide and catalytic amounts of Ni(acac)2 species and bipyridyl ligand at 145 oC, we
Intrigued by the initial results, we tried to leverage the reactivity of nickel catalysis for valuable organic transformations. Specifically, a direct hydrocyanation of alkynes was first examined to afford vinyl nitriles, which are a versatile synthetic building unit (Table 1).13 Indeed, the desired product, 2,3-diphenylacrylonitrile (3a), was obtained in 18% yield (Z-/E-isomers, 1:1) from a reaction of diphenylacetylene in formamide and anisole when Ni(acac)2 was employed (5 mol %) in the presence of Xanphos (15 mol %) at 150 oC for 12 h (entry 1). While an increase of catalyst loading improved the product yield to some extent (entry 2), we found that additives displayed
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ACS Catalysis
significant influence on the reactivity. Inspired by Konwar and Maffioli’s finding that Lewis acids can facilitate the dehydration of amides,14 an array of additives was examined subsequently. While aluminum or tin species (10 mol %) improved product yields moderately (entries 35), a reaction in the presence of Co(acac)2 additive gave much higher efficiency, leading to 3a in 90% yield (entry 6). While the nature of cobalt species was crucial in this catalytic reaction (entry 7), cobalt alone did not mediate the cyanation (entry 8). Reaction at lower temperature resulted in a sharp decrease in product yield (entry 9). Nickel catalysts other than Ni(acac)2 were less effective for the current transformation (entries 1012). While a similar ligand effect of bipyridine was observed when it compared to Xantphos in the absence of additives (entry 13), the latter one was much more effective in combination with cobalt species (entry 14).
(1r) substituted ethynes were also viable for this Nicatalyzed cyanation reaction. It is noteworthy that while an almost equal mixture of stereoisomers (E/Z) was produced from the reaction of diarylacetylenes, E-isomeric product (E-3r) was formed exclusively from the hydrocyanation of dibutylacetylene (1r) although the exact pathway is not understood at the present stage. Table 2. Scope of the alkynes for the hydrocyanation a
R +
R
H
O C
Ni(acac)2 (5 mol %) Co(acac)2 (10 mol %) Xantphos (15 mol %)
NH2
1a-1r
Table 1. Optimization of the alkyne hydrocyanation a
Ph +
Ph 1a
entry
H
O C
Ni catalyst Xantphos (15 mol %) additive (10 mol %)
NH2
2
[Ni] (mol %)
PhOCH3 150 oC, 24 h
CN
CN Ph
Ph
R1
3a
additive (mol %)
yield of 3a (%) 1 Ni(acac)2 (5) 18 Ni(acac)2 (25) 50 2b 3 Ni(acac)2 (5) AlCl3 (10) 31 4 Ni(acac)2 (5) Al(iBu)3 (10) 52 5 Ni(acac)2 (5) SnCl2·2H2O (10) 37 6 Ni(acac)2 (5) Co(acac)2 (10) 90 7 Ni(acac)2 (5) CoCl2 (10) 60 8 Co(acac)2 (10)
