Palladium-Catalyzed Synthesis of α-Iminonitriles from Aryl Halides via Isocyanide Double Insertion Reaction

Article abstract of DOI:10.1021/acs.joc.5b02777

An efficient one-pot synthesis of α-iminonitriles from readily available aryl halides via palladium-catalyzed double isocyanide insertion and elimination has been developed, without using various hypertoxic cyanides and excess oxidants. Furthermore, the utility of this reaction was demonstrated by the rapid total synthesis of quinoxaline and the reaction of functional groups exchanged with aryl halides. (Chemical Equation Presented).

Full text of DOI:10.1021/acs.joc.5b02777

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Article
Palladium-Catalyzed Synthesis of alpha-Iminonitriles from
Aryl Halides via Isocyanide Double Insertion Reaction
Zhen-Bang Chen, Ying Zhang, Qing Yuan, Fang-Ling Zhang, Yong-Ming Zhu, and Jing-Kang Shen
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.5b02777 • Publication Date (Web): 27 Jan 2016
Downloaded from http://pubs.acs.org on February 2, 2016
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Palladium-Catalyzed Synthesis of α-Iminonitriles from Aryl
Halides via Isocyanide Double Insertion Reaction
Zhen-Bang Chen,† Ying Zhang,† Qing Yuan,† Fang-Ling Zhang,† Yong-Ming Zhu,*,† and
Jing-Kang Shen*,‡
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†College of Pharmaceutical Sciences, Soochow University, Suzhou, 215123, China
‡Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203,
China
ABSTRACT
An efficient one-pot synthesis of α-iminonitriles from readily available aryl halides via
palladium-catalyzed double isocyanide insertion and elimination has been developed,
without using various hypertoxic cyanides and excess oxidants. Furthermore, the utility of
this reaction was demonstrated by the rapid total synthesis of quinoxalin and the reaction of
functional groups exchange with aryl halides.
INTRODUCTION
Isocyanides are an important class of organic molecules which have been widely applied
in organic, medicinal and combinatorial chemistry since the Passerini and Ugi reactions
were discovered.1 In the past decade, isocyanides have emerged as versatile C1 building
blocks to build C-C,2 C-N,3,4 and C-O5 bonds in palladium-catalyzed two-component
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reaction and evolutionary multicomponent reactions (MCRs). Recently, tert-butyl
isocyanide as a cyanide alternative have been reported,6 which further broadened the
application of isocyanides in organic synthesis. During the last few years, our group have
synthesized many kinds of organic compounds including isocoumarins, phthalides,5c
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quinazolinones,3e diazoles,4c indenoindolones,2h
alkynones,2c
indane-1,3-dione,2f
diarylketones,2g and aryl aldehydes7 via palladium-catalyzed isocyanide insertion into C−X
bonds (X=Br, I). Nevertheless, the most reported achievements mainly focus on the utility
of isocyanides single insertion for the synthesis of nitrogen-containing compounds. Readily
polymerized in the presence of transition metal,8 isocyanides were seldomly used for
multiple insertion reaction, especially for the reaction of isocyanides multiple insertion at
the same site. Only a few examples of metal-catalyzed double isocyanides insertion have
been reported. For instance, in 1991, Yamamoto and co-workers9 reported double insertion
of isocyanides into a metal-carbon bond through cobalt-catalyzed (scheme 1, a). In 2004,
Whitby et al.10 reported palladium-catalyzed double isocyanides insertion into aryl
bromides for the synthesis of α-iminoimidates (scheme 1, b). Recently, Tu and Jiang
developed a palladium-catalyzed3c or cobalt(II)/silver relay catalyzed11 isocyanides double
insertion intramolecular cyclization for the formation of indole derivatives (scheme 1, c).
Subsequently, Ogawa and co-workers12 achieved isocyanides double insertion into Pd-C
bond for the synthesis of α-diimines (scheme 1, d). Obviously, with the powerful
development space and potential application, transition-metal-catalyzed isocyanides
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multiple insertion reactions have increasingly attracted the attention of more and more
chemists.
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Scheme 1. Metal-Catalyzed Isocyanide Double Insertion Reaction
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The α-iminonitriles (imidoyl cyanides) are an valuable class of synthetic intermediates,13
which could not only serve as precursors for α-ketoacids, amides, N-alkylketene-imines,
triazoles, aminopyrroles, diimines and dicarbonyl (scheme 2), but also provide a rapid and
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valid access to build the construction of nitrogen heterocycles in cycloadditions.14 Moreover,
the α-iminonitriles are quite stable to high temperature (greater than 100oC) and water,
which make them as an effective substitute for acylnitriles to participate in metal-catalyzed
C–CN activation.15 In addition to its widespread use in organic transformation,
α-iminonitriles also exhibit diverse biological activities, such as inhibit the function of
histamine-induced or acetylcholine-induced contraction in rat ileum.16 As a result, many
methodologies have been reported for the synthesis of α-iminonitriles.7a,13a,17 However, most
of them are multistep reactions, use complex substrates, excess oxidants and various toxic
cyanides such as Bu3SnCN, Hg(CN)2, NaCN, CuCN and so on. Herein, we provide a new
protocol for the synthesis of α-iminonitrile via palladium-catalyzed double isocyanide
insertion in one pot (scheme 1, e), of note is that the protocol employs no hypertoxic
cyanides.
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Scheme 2. Application of α-Iminonitrile
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RESULTS AND DISCUSSION
Initiated investigation was performed by using 4-iodobiphenyl 1a and tert-butyl
isocyanide in the presence of Pd(OAc)2 and PCy3 with K2CO3 as base, when the reaction
was carried out in the solvent of dimethyl sulfoxide (DMSO) under nitrogen at 120oC for 12
h, the desired product 2a was found in 31% yield (Table 1, entry 1), along with minor
amounts of 2aa and 2ab (scheme 3), however, almost half of 1a were remained. Prolonged
reaction time increased the yield to 44% ( Table 1, entry 2 ).
Scheme 3. Byproducts in the Synthetic Reaction of 2a.
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Considering that water resulted in the formation of 2ab, we used molecular sieves (4A
MS) as additive under argon, the yield was up to 57% (Table 1, entry 3). Raising the
temperature led to an increase in the yield (Table 1, entry 3-5). Solvent screening showed
that N,N-dimethylformamide (DMF) was optimal (Table 1, entry 5-8). Then, several bases
were tested, as the base weaken, the yield of byproduct 2aa increased, when the base was
switched to Cs2CO3, to our surprise, the yield was improved to 79% (Table 1, entry 11).
Subsequently, other palladium sources also were investigated, however, none of them were
superior to PdCl2 (Table 1, entry 15-16). Phosphines played a pivotal role in the reaction.
We conducted the reaction with using other mono- or diphosphines, the yield of using
monophosphines was superior to diphosphines and higher yield was obtained when using
PCy3 (Table 1, entry 17-21). Eventually, the optimized reaction conditions were PdCl2 (10
mol %) and PCy3 (20 mol %) as catalyst system, with Cs2CO3 (2 equiv) as base and DMF as
solvent and 4A MS as additive under argon at 135oC.
Table 1. Optimization of Reaction Conditionsa
Entry
Catalyst
Ligand
Base
Additive
Solvent
Yield[%]b
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1
2
Pd(OAc)2
Pd(OAc)2
PCy3
PCy3
K2CO3
K2CO3
---
---
DMSO
DMSO
31c
44d
3
4
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
PdCl2
PCy3
PCy3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
NaOAc
Na2CO3
Cs2CO3
K3PO4
4A MS
4A MS
4A MS
4A MS
4A MS
4A MS
4A MS
4A MS
4A MS
4A MS
4A MS
4A MS
4A MS
4A MS
4A MS
4A MS
4A MS
4A MS
4A MS
DMSO
DMSO
DMSO
dioxane
toluene
DMF
57e
41f
65
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5
PCy3
6
PCy3
19
7
PCy3
22
8
PCy3
61
9
PCy3
DMF
trace
31
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PCy3
DMF
PCy3
DMF
79
PCy3
DMF
60
PCy3
Na2OtBu
DBU
DMF
44
PCy3
DMF
trace
87
PCy3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
DMF
DMF
Pd2(dba)3
PdCl2
PCy3
52
PPh3
DMF
79
PdCl2
(R)-BINAP
BuPAd2
DPPP
DPEphos
DMF
22
PdCl2
DMF
53
PdCl2
DMF
17
21
PdCl2
DMF
39
a
Reaction conditions: All reactions were performed under argon with 1a (0.5
mmol), tert-butyl isocyanide (1.5 mmol), catalyst (0.05 mmol), ligand (0.1 mmol),
base (1 mmol) and additive (100 mg) in 2 mL of solvent at 135 °C for 18 h in a sealed
tube. Isolated yield. Under N2 at 120oC for 12 h. Under N2 at 120oC for 18 h.
b
c
d
e
120oC. f 100oC.
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With the optimized conditions in hand, then, the substrate scope and limitations of this
methodology was explored. As illustrated in Table 2, aryl iodides with electron -rich, -poor
substituents (2d-2f, 2k, 2o-2q, 2g-2j, 2l), aryl bromides (2x-2y) as well as α, β-unsaturated
aryl bromide ( 2z ) were all compatible with the method, affording the respective products
in moderate to excellent yields, and also, electron-poor phenyl halides afforded higher
yields than their electron-rich counterparts. 2-Methyliodobenzene gave product only in 33%
yield (2c), which resulted from the steric hindrance in the ortho-position. In addition, the
method tolerates a variety of functional groups, such as halogen, ketone (2m), ester (2n),
ether (2o, 2q), also leading to the corresponding products in good yields. Unfortunately,
several sensitive groups such as phenolic hydroxy and aromatic amino were incompatible.
Interestingly, 4-iodophenylmethanol (2r) could be converted into the corresponding
α-iminonitrile in 86% yield. In addition, heteroaryl halides (2s-2u, 2y) also gave good
results in the standard conditions. Meanwhile, the 1,3-diiodobenzene was converted into
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N,N'-di-tert-butylisophthalimidoyl cyanide in 31% yield (2w).
Table 2. Palladium-Catalyzed Synthesis of α-Iminonitriles a
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2a, 87%(65%b)
2b, 77%
2f, 69%
2j, 92%
2c, 32%
2g, 86%
2k, 71%
2o, 65%
2s, 88%
2d, 80%
2h, 87%
2l, 55%
2p, 50%
2t, 67%
2e, 70%
2i, 83%
2m, 57%
2n, 65%
2r, 86%
2q, 78%
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2u, 92%
2v, 49%
2wc, 30%
2xd, 65%
2yd, 62%
2zd, 44%
a All reactions were performed under argon with aryl iodides (0.5 mmol), tert-butyl
isocyanide (1.5 mmol), catalyst (0.05 mmol), ligand (0.1 mmol), base (1 mmol) and
additive (100 mg) in 2 mL of solvent at 135 °C for 18 h in a sealed tube; isolated
yields. b Using 4-bromobiphenyl instead of 4-iodobiphenyl. c Aryl halides (0.5 mmol),
tert-butyl isocyanide (3 mmol), catalyst (0.1 mmol), ligand (0.2 mmol), base (2
mmol) and additive (100 mg) in 2 mL of solvent. d Aryl bromides.
To extend the application of this reaction, various substituted isocyanides such as
cyclohexyl (3a), phenylethyl (3b), 1-adamantyl (3c) 1,1,3,3-tetramethylbutyl (3d)
isocyanides were investigated. Unfortunately, only the 1,1,3,3-tetramethylbutyl isocyanide
could
smoothly
be
transformed,
giving
N-(2,4,4-trimethylpentan-2-yl)-[1,1'-biphenyl]-4-carbimidoyl cyanide (3d) in 71% yield
(Scheme 4). The results suggested the importance of the quaternary carbon. In addition, the
steric hindrance of isocyanides with different substituent has large influence on this kind of
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reaction, and we consider that 3d and tert-butyl isocyanide are more prone to eliminate to
transformation into cyano.
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Scheme 4. Scope of Isocyanide Double Insertion
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Next, to further explore the synthetic utility of our methodology, we performed a number
of preliminary experiments as depicted in scheme 5. When 2 was refluxed under acetic acid
with 1,2-phenylenediamine in the presence of NaOAc, 3-phenylquinoxalin-2-amine (4a)
was formed in 77% yield (scheme 5, eq 1). And also, benzonitrilic compound (2oa) was
formed in 74% yield (scheme 5, eq 2) with dissolving iodobenzene and 2 in DMSO in the
presence of Pd(OAc)2 and Cu(TFA)2 at 120oC, which showed that 2 could be used as cyano
source, and the further studies are underway in our laboratory. The compounds of 4a are
common building blocks found in many biologically and pharmaceutically compounds,18
and the compounds of 2oa are important intermediates in organic synthesis.19
Scheme 5. Transformation of 2
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Based on the basis of literature reports,3c,6,10 a plausible mechanism for this reaction is
depicted in Scheme 6. First, oxidative addition of 1 to the Pd(0) catalyst lead to the
palladium complex A, followed by tert-butyl isocyanide insertion to form intermediate B.
Subsequently, the second isocyanide insertion takes place to form intermediate C. With the
assistance of Cs2CO3, intermediate C undergoes tert-butyl elimination and Pd expulsion to
form the product 2.
Scheme 6. Plausible Reaction Mechanism
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CONCLUSION
In summary, we have illustrated a simple and efficient approach for palladium-catalyzed
synthesis of α-iminonitrile via tert-butyl isocyanide double insertion and elimination in one
pot. In this reaction, we overcame the challenge of isocyanides polymerization in the
presence of transition metal in double isocyanides insertion, and achieved isocyanides as
cyano source without any oxidants. Compared to others methods, the reaction is tolerant of
a wide range of substrates and is more efficient, convenient, low-toxic for the synthesis of
α-iminonitrile.
EXPERIMENTAL SECTION
General Information. Reactants and reagents were purchased from commercial
suppliers. All solvents were dried and freshly distilled. TLC was performed on silica
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HSGF254 plates. Melting points were determined with a digital melting-point apparatus.
NMR spectra were run in a solution of deuterated chloroform (CDCl3) with
tetramethylsilane (TMS) as internal standard and were reported in parts per million (ppm).
1H and 13C NMR spectra were obtained at 400/101 MHz (1H/13C), respectively.
High-resolution mass spectra (HRMS) analyses were carried out on a chemical ionization
(CI) apparatus using time-of-flight (TOF) mass spectrometry. Infrared (IR) obtained
using KBr tablets and wavenumbers in cm−1.
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General procedure for the synthesis of α-Iminonitrile. 1 (0.5 mmol), tert-butyl
isocyanide (1.5 mmol), PdCl2 (0.05 mmol), PCy3 (0.1 mmol), Cs2CO3 (1.0 mmol) and 4A
MS (100 mg) were added into a 15 ml sealed tube equipped with a magnetic stirring bar.
The mixture was stirred in DMF (2 mL) under argon at 135 °C for 18 h. After completion of
the reaction as indicated by TLC, poured in to water (30 mL) and extracted by ethyl acetate
(3×30 mL). The combined organic layers were dried (Na2SO4) and evaporated. The residue
was purified on a silica gel column using petroleum ether/EtOAc as the eluent to give the
pure target product.
Preparation of 3-Phenylquinoxalin-2-amine (4a). To a solution of 2 (0.4 mmol),
1,2-phenylenediamine (0.6 mmol) and NaOAc (1 mmol) in AcOH (4 mL) in a round
bottom flask. The reaction mixture was refluxed for 2 h. After cooling to room temperature,
concentrated in vacuo, then washed with brine and extracted with DCM (10 mL × 3). The
combined organic phases dried over anhydrous Na2SO4 and evaporated. The residue was
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purified on a silica gel column using petroleum ether/EtOAc as the eluent to give the pure
target product.
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Preparation of 4-Methoxybenzonitrile (2oa). 1-Iodo-4-methoxybenzene (0.3 mmol),
2a (0.45 mmol ), Pd(OAc)2 (0.05 mmol), Cu(TFA)2 (0.6 mmol) were added into a 15 ml
sealed tube equipped with a magnetic stirring bar. The mixture was stirred in DMSO (1.5
mL) at 120 °C for 10 h. After completion of the reaction as indicated by TLC, poured in to
water (30 mL) and extracted by ethyl acetate (3×30 mL). The combined organic layers were
dried (Na2SO4) and evaporated. The residue was purified on a silica gel column using
petroleum ether/EtOAc as the eluent to give the pure target product.
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N-(tert-Butyl)-[1,1'-biphenyl]-4-carbimidoyl cyanide (2a). White solid (114 mg, 87%
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yield). Mp: 91-93 C. H NMR (400 MHz, CDCl3) δ 8.05 (d, J = 7.9 Hz, 2H), 7.66 (d, J =
7.9 Hz, 2H), 7.61 (d, J = 7.4 Hz, 2H), 7.45 (t, J = 7.3 Hz, 2H), 7.38 (t, J = 7.1 Hz, 1H), 1.54
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(s, 9H). C NMR (101 MHz, CDCl3) δ 144.6 (s), 140.0 (s), 134.3 (s), 129.1 (s), 128.2 (s),
127.7 (s), 127.4 (s), 127.3 (s), 111.9 (s), 58.6 (s), 29.5 (s). IR (KBr): ν 2971, 2918, 2213,
1669, 1592, 1475, 1363, 1205, 1181, 999, 843 cm-1. HRMS (CI): m/z calcd for C18H19N2
[M+H]+, 263.1548 ; found, 263.1555.
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N-(tert-Butyl)-benzimidoyl cyanide (2b).17a Yellow oil (72mg, 77% yield). H NMR
(400 MHz, CDCl3) δ 7.99 (d, J = 7.4 Hz, 2H), 7.53 – 7.41 (m, 3H), 1.54 (s, 9H).13C NMR
(101 MHz, CDCl3) δ 136.8 (s), 131.8 (s), 128.8 (s), 127.3 (s), 111.8 (s), 58.5 (s), 29.5 (s).
HRMS (CI): m/z calcd for C12H14N2 [M+H]+, 186.1157 ; found, 186.1154.
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N-(tert-Butyl)-2-methylbenzimidoyl cyanide (2c). Colorless oil (32 mg, 32% yield). H
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Hz, 1H), 2.49 (s, 3H), 1.55 (s, 9H). C NMR (101 MHz, CDCl3) δ 137.8 (s), 137.2 (s),
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135.4 (s), 131.9(s), 130.5 (s), 129.3 (s), 126.4 (s), 112.6(s), 59.2 (s), 29.5 (s), 21.0 (s). IR
(KBr): ν 2970, 2926, 2856, 2212, 1676, 1615, 1457, 1363, 1202, 990, 878, 756, 722 cm-1.
HRMS (CI): m/z calcd for C13H17N2 [M+H]+, 201.1392 ; found, 201.1385.
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N-(tert-Butyl)-3-methylbenzimidoyl cyanide (2d). Yellow oil (80mg, 80% yield). H
NMR (400 MHz, CDCl3) δ 7.80 (d, J = 6.8 Hz, 2H), 7.34 (q, J = 7.7 Hz, 2H), 2.42 (s, 3H),
1.55 (s, 9H). 13C NMR (101 MHz, CDCl3) δ 138.7 (s), 137.0 (s), 135.3 (s), 132.6 (s), 128.7
(s), 127.6 (s), 124.6 (s), 111.9 (s), 58.4 (s), 29.4 (s), 21.5 (s). IR (KBr): ν 2972, 2929, 2872,
2216, 1603, 1585, 1460, 1304, 1206, 1020, 790, 700 cm-1. HRMS (CI): m/z calcd for
C13H17N2 [M+H]+, 201.1392 ; found, 201.1395.
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N-(tert-Butyl)-4-methylbenzimidoyl cyanide (2e).17a. Colorless oil (70mg 70% yield). H
NMR (400 MHz, CDCl3) δ 7.87 (d, J = 8.3 Hz, 2H), 7.24 (d, J = 8.2 Hz, 2H), 2.40 (s, 3H),
1.52 (s, 9H). 13C NMR (101 MHz, CDCl3) δ 142.4 (s), 136.7 (s), 132.9 (s), 129.5 (s), 127.2
(s), 112.0 (s), 58.3 (s), 29.5 (s), 21.6 (s). HRMS (CI): m/z calcd for C13H17N2 [M+H]+,
201.1392 ; found, 201.1389.
N,4-Di-tert-butylbenzimidoyl cyanide (2f). White solid (83mg, 69% yield) Mp: 47-48oC.
1H NMR (400 MHz, CDCl3) δ 7.94 (d, J = 8.5 Hz, 2H), 7.49 (d, J = 8.5 Hz, 2H), 1.54 (s,
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9H), 1.36 (s, 9H). C NMR (101 MHz, CDCl3) δ 155.5 (s), 136.6 (s), 132.8 (s), 127.1 (s),
125.8 (s), 111.9 (s), 58.3 (s), 35.1 (s), 31.2 (s), 29.5 (s). IR (KBr): ν 2965, 2926, 2869, 2211,
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1612, 1595, 1462, 1362, 1266, 1204, 999, 837, 657 cm-1. HRMS (CI): m/z calcd for
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C16H23N2 [M+H]+, 243.1861 ; found, 243.1835.
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N-(tert-Butyl)-4-chlorobenzimidoyl cyanide (2g)17c. Yellow oil (95mg, 86% yield). H
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NMR (400 MHz, CDCl3) δ 7.92 (d, J = 8.3 Hz, 2H), 7.42 (d, J = 8.3 Hz, 2H), 1.53 (s, 9H).
13C NMR (101 MHz, CDCl3) δ 138.2 (s), 135.7 (s), 133.8 (s), 129.1 (s), 128.5 (s), 111.5 (s),
58.7 (s), 29.4 (s). HRMS (CI): m/z calcd for C12H14N2Cl [M+H]+, 221.0846 ; found,
221.0851.
N-(tert-Butyl)-4-fluorobenzimidoyl cyanide (2h). Yellow oil (90mg, 87% yield). 1H NMR
(400 MHz, CDCl3) δ 7.99 (ddd, J = 8.8, 5.3, 1.6 Hz, 2H), 7.17 – 7.10 (m, 2H), 1.52 (d, J =
1.6 Hz, 9H).13C NMR (101 MHz, CDCl3) δ 166.4 (s), 163.9 (s), 135.5 (s), 131.7 (d, J = 3.1
Hz), 129.5 (d, J = 8.9 Hz), 116.1 (s), 115.9 (s), 111.7 (s), 58.6 (s), 29.5 (s). IR (KBr): ν
2972, 2927, 2855, 2215, 1614, 1601, 1588, 1507, 1230, 1156, 842 cm-1. HRMS (CI): m/z
calcd for C12H14N2F [M+H]+, 205.1141 ; found, 205.1133.
N-(tert-Butyl)-4-(trifluoromethyl)benzimidoyl cyanide (2i). White solid (105mg, 83%
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yield). Mp: 59-61oC. H NMR (400 MHz, CDCl3) δ 8.11 (d, J = 8.2 Hz, 2H), 7.71 (d, J =
8.3 Hz, 2H), 1.55 (s, 9H). 13C NMR (101 MHz, CDCl3) δ 138.28 (s), 135.64 (s), 133.98 (s),
133.65 (s), 133.33 (s), 133.00 (s), 127.69 (s), 125.85 (t, J = 5.7 Hz), 125.18 (s), 122.47 (s),
119.77 (s), 111.43 (s), 59.22 (s), 29.42 (s). IR (KBr): ν 2972, 2927, 2855, 2216, 1639, 1618,
1460, 1324, 1164, 1126, 1013 cm-1. HRMS (CI): m/z calcd for C13H14N2F3 [M+H]+,
255.1109 ; found, 255.1120.
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N-(tert-Butyl)-4-(1H-pyrrol-1-yl)benzimidoyl cyanide (2j). White solid (115mg, 92%
yield).Mp: 77-79oC. 1H NMR (400 MHz, CDCl3) δ 8.06 (d, J = 8.6 Hz, 2H), 7.47 (d, J = 8.6
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Hz, 2H), 7.19 – 7.16 (m, 2H), 6.42 – 6.39 (m, 2H), 1.56 (s, 9H). C NMR (101 MHz,
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CDCl3) δ 143.2 (s), 135.8 (s), 132.4 (s), 128.8 (s), 119.8 (s), 119.1 (s), 111.7 (s), 111.5 (s),
58.6 (s), 29.5 (s). IR (KBr): ν 2967, 2919, 2850, 2226, 1669, 1604, 1519, 1477, 1334, 1183,
1066, 842, 723 cm-1. HRMS (CI): m/z calcd for C16H18N3 [M+H]+, 252.1501 ; found,
252.1497.
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N-(tert-Butyl)-3,5-dimethylbenzimidoyl cyanide (2k). Yellow oil (76mg, 71% yield). H
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NMR (400 MHz, CDCl3) δ 7.59 (s, 2H), 7.13 (s, 1H), 2.37 (s, 6H), 1.53 (s, 9H). C NMR
(101 MHz, CDCl3) δ 138.6 (s), 137.2 (s), 135.4 (s), 133.6 (s), 125.0 (s), 112.0 (s), 58.4 (s),
29.5 (s), 21.3 (s). IR (KBr): ν 2996, 2970, 2922, 2869, 2214, 1601, 1588, 1457, 1363, 1183,
1160, 856, 704 cm-1.HRMS (CI): m/z calcd for C14H19N2 [M+H]+, 215.1548 ; found,
215.1542.
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N-(tert-Butyl)-3,5-difluorobenzimidoyl cyanide (2l). Yellow oil (61mg, 55% yield). H
NMR (400 MHz, CDCl3) δ 7.53 (d, J = 2.4 Hz, 2H), 6.96 (d, J = 7.3 Hz, 1H), 1.53 (s, 9H).
13C NMR (101 MHz, CDCl3) δ 164.47 (d, J = 12.3 Hz), 161.99 (d, J = 12.3 Hz), 138.51 (t, J
= 9.2 Hz), 134.66 (t, J = 4.0 Hz), 111.16 (s), 110.63 – 110.15 (m), 107.44 (s), 107.19 (s),
106.93 (s), 59.24 (s), 29.39 (s). IR (KBr): ν 2955, 2921, 2852, 2215, 1620, 1594, 1460,
1329, 1123, 992 cm-1.HRMS (CI): m/z calcd for C12H13N2F2 [M+H]+, 223.1047 ; found,
223.1035.
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4-Acetyl-N-(tert-butyl)benzimidoyl cyanide (2m). Yellow solid (65mg, 57% yield). Mp:
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87-88oC. H NMR (400 MHz, CDCl3) δ 8.06 (d, J = 8.6 Hz, 2H), 8.00 (d, J = 8.6 Hz, 2H),
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2.63 (s, 3H), 1.53 (s, 9H). C NMR (101 MHz, CDCl3) δ 197.5 (s), 139.3 (s), 138.9 (s),
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136.0 (s), 128.7 (s), 127.5 (s), 111.5 (s), 59.1 (s), 29.4 (s), 27.0 (s). IR (KBr): ν 2972, 2917,
2850, 2600, 2218, 1685, 1607, 1592, 1420, 1366, 1260, 1204, 1005, 954, 851, 835, 671
cm-1. HRMS (CI): m/z calcd for C14H17N2O [M+H]+, 229.1341 ; found, 229.1335.
Methyl 4-((tert-butylimino)(cyano)methyl)benzoate (2n). Yellow solid (79mg, 65% yield).
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Mp: 79-80oC. H NMR (400 MHz, CDCl3) δ 8.10 (d, J = 8.5 Hz, 2H), 8.04 (d, J = 8.3 Hz,
2H), 3.94 (s, 3H), 1.53 (s, 9H). 13C NMR (101 MHz, CDCl3) δ 166.4 (s), 138.9 (s), 136.1 (s),
132.9 (s), 130.0 (s), 127.3 (s), 111.5 (s), 59.1 (s), 52.5 (s), 29.4 (s). IR (KBr): ν 3067, 2994,
2971, 2949, 2219, 1719, 1613, 1593, 1265, 1204, 1106, 871, 776, 700 cm-1.HRMS (CI): m/z
calcd for C14H17N2O2 [M+H]+, 245.1290 ; found, 245.1287.
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N-(tert-Butyl)-4-methoxybenzimidoyl cyanide (2o)17a. Yellow oil (70mg, 65% yield). H
NMR (400 MHz, CDCl3) δ 7.93 (d, J = 8.7 Hz, 2H), 6.94 (d, J = 8.8 Hz, 2H), 3.86 (s, 3H),
1.52 (s, 9H).13C NMR (101 MHz, CDCl3) δ 162.6 (s), 136.1 (s), 128.9 (s), 128.4 (s), 114.1
(s), 111.9 (s), 58.0 (s), 55.5 (s), 29.5 (s). HRMS (CI): m/z calcd for C13H17N2O [M+H]+,
217.1341 ; found, 217.1338.
N-(tert-Butyl)-2,3-dihydrobenzo[b][1,4]dioxine-6-carbimidoyl cyanide (2p). Yellow oil
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(61mg, 50% yield). H NMR (400 MHz, CDCl3) δ 7.53 (d, J = 2.1 Hz, 1H), 7.48 (dd, J =
8.5, 2.1 Hz, 1H), 6.91 (d, J = 8.5 Hz, 1H), 4.29 (d, J = 5.1 Hz, 2H), 4.27 (d, J = 5.1 Hz, 2H),
1.50 (s, 9H). 13C NMR (101 MHz, CDCl3) δ 147.0 (s), 143.8 (s), 135.8 (s), 129.2 (s), 121.0
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(s), 117.5 (s), 116.1 (s), 111.8 (s), 64.7 (s), 64.3 (s), 58.1 (s), 29.5 (s). IR (KBr): ν 2969,
2932, 2877, 2216, 1666, 1579, 1504, 1291, 1065, 889 cm-1. HRMS (CI): m/z calcd for
C14H17N2O2 [M+H]+, 245.1290 ; found, 245.1293..
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N-(tert-Butyl)-3,5-dimethoxybenzimidoyl cyanide (2q). White solid (96mg,78% yield).
Mp: 99-101oC. 1H NMR (400 MHz, CDCl3) δ 7.14 (d, J = 2.0 Hz, 2H), 6.59 (s, 1H), 3.84 (s,
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6H), 1.52 (s, 9H). C NMR (101 MHz, CDCl3) δ 161.1 (s), 137.4 (s), 136.7 (s), 111.8 (s),
105.2 (s), 104.3 (s), 58.6 (s), 55.7 (s), 29.5 (s). IR (KBr): ν 2976, 2939, 2833, 2212, 1606,
1586, 1458, 1308, 1207, 1154, 1066, 1021 cm-1. HRMS (CI): m/z calcd for C14H19N2O2
[M+H]+, 247.1447 ; found, 247.1452.
N-(tert-Butyl)-4-(hydroxymethyl)benzimidoyl cyanide (2r). Yellow oil (93mg, 86% yield).
1H NMR (400 MHz, CDCl3) δ 7.96 (d, J = 8.1 Hz, 2H), 7.43 (d, J = 8.1 Hz, 2H), 4.75 (s,
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2H), 1.52 (s, 9H). C NMR (101 MHz, CDCl3) δ 144.9 (s), 136.5 (s), 134.7 (s), 127.5 (s),
127.0 (s), 111.9 (s), 64.8 (s), 58.6 (s), 29.5 (s). IR (KBr): ν 3348, 2971, 2932, 2858, 2214,
1721, 1594, 1572, 1364, 1264, 1203, 1004, 825, 676 cm-1. HRMS (CI): m/z calcd for
C13H17N2O [M+H]+, 217.1341; found, 217.1342.
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N-(tert-Butyl)isonicotinimidoyl cyanide (2s). Yellow oil (82mg, 88% yield). H NMR
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(400 MHz, CDCl3) δ 8.74 (d, J = 4.5 Hz, 2H), 7.82 (d, J = 4.5 Hz, 2H), 1.52 (s, 9H). C
NMR (101 MHz, CDCl3) δ 150.7 (s), 142.0(s), 135.4 (s), 120.8 (s), 111.0 (s), 59.6 (s), 29.4
(s). IR (KBr): ν 2966, 2928, 2853, 2215, 1703, 1614, 1593, 1408, 1364, 1278, 1218, 1188,
1008, 988 cm-1. HRMS (CI): m/z calcd for C11H14N3 [M+H]+, 188.1188 ; found,188.1184.
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N-(tert-Butyl)thiophene-2-carbimidoyl cyanide (2t). Yellow oil (64mg, 67% yield) H
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1H), 1.49 (s, 9H). C NMR (101 MHz, CDCl3) δ 143.1 (s), 130.9 (d, J = 11.3 Hz), 127.9
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(s), 111.3 (s), 58.5 (s), 29.6 (s). IR (KBr): ν 2971, 2925, 2854, 2218, 1654, 1597, 1580,
1425, 1364, 1203, 955, 850, 711 cm-1. HRMS (CI): m/z calcd for C10H13N2S [M+H]+,
193.0799 ; found, 193.0787.
N-(tert-Butyl)picolinimidoyl cyanide (2u). Yellow solid (99mg, 92%yield). Mp: 35-37oC.
1H NMR (400 MHz, CDCl3) δ 8.71 (d, J = 5.6 Hz, 1H), 8.04 (d, J = 8.0 Hz, 1H), 7.75 (t, J =
13
8.3 Hz, 1H), 7.41 – 7.36 (m, 1H), 1.54 (s, 9H). C NMR (101 MHz, CDCl3) δ 153.2 (s),
149.4 (s), 138.4 (s), 136.9 (s), 125.8 (s), 121.0 (s), 111.8 (s), 58.9 (s), 29.3 (s). IR (KBr): ν
2971, 2924, 2853, 2220, 1620, 1604, 1583, 1464, 1364, 1207, 1012, 793, 742 cm-1. HRMS
(CI): m/z calcd for C11H14N3 [M+H]+, 188.1188 ; found, 188.1176.
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N-(tert-Butyl)-1-naphthimidoyl cyanide (2v). Yellow oil (58mg, 49% yield). H NMR
(400 MHz, CDCl3) δ 8.69 (d, J = 8.4 Hz, 1H), 7.98 – 7.89 (m, 3H), 7.62 – 7.53 (m, 3H),
1.66 (s, 9H). 13C NMR (101 MHz, CDCl3) δ 137.7 (s), 134.2 (s), 132.6 (s), 132.0 (s), 130.2
(s), 128.9 (d, J = 8.5 Hz), 127.9 (s), 126.7 (s), 124.9 (d, J = 2.7 Hz), 112.9 (s), 59.5 (s), 29.6
(s). IR (KBr): ν 2970, 2927, 2854, 2222, 1611, 1590, 1510, 1364, 1202, 954, 801, 772 cm-1.
HRMS (CI): m/z calcd for C16H17N2 [M+H]+, 237.1392 ; found, 237.1388.
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N,N'-Di-tert-butylisophthalimidoyl cyanide (2w). Colorless oil (43mg,30% yield). H
NMR (400 MHz, CDCl3) δ 8.85 (s, 1H), 8.39 (dd, J = 7.8, 1.7 Hz, 2H), 7.83 (t, J = 7.8 Hz,
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1H), 1.83 (s, 18H). C NMR (101 MHz, CDCl3) δ 136.0 (d, J = 4.7 Hz), 130.3 (s), 129.3
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(s), 125.8 (s), 111.5 (s), 59.0 (s), 29.4 (s). IR (KBr): ν 2972, 2926, 2854, 2217, 1607, 1582,
1462, 1365, 1190, 1031, 806, 690 cm-1. HRMS (CI): m/z calcd for C18H23N4 [M+H]+,
295.1923 ; found, 295.1919.
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N-(tert-Butyl)-2-naphthimidoyl cyanide (2x). White solid (77mg,65% yield). Mp:
50-53oC. 1H NMR (400 MHz, CDCl3) δ 8.44 (s, 1H), 8.13 (d, J = 8.7 Hz, 1H), 7.97 (d, J =
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8.4 Hz, 1H), 7.87 (d, J = 8.3 Hz, 2H), 7.60 – 7.54 (m, 2H), 1.60 (s, 9H). C NMR (101
MHz, CDCl3) δ 136.9 (s), 135.1 (s), 133.0 (s), 132.9 (s), 129.3 (s), 129.2 (s), 128.7 (s),
128.1 (s), 127.9 (s), 127.0 (s), 122.8 (s), 111.9 (s), 58.6 (s), 29.6 (s). IR (KBr): ν 2972, 2921,
2851, 2215, 1596, 1459, 1361, 1277, 1187, 1124, 862, 820, 751 cm-1. HRMS (CI): m/z
calcd for C16H17N2 [M+H]+, 237.1392 ; found, 237.1386.
N-(tert-Butyl)-3a,7a-dihydrobenzo[b]thiophene-3-carbimidoyl cyanide (2y). White solid
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(75mg, 62% yield). Mp:76-78oC. H NMR (400 MHz, CDCl3) δ 8.85 (d, J = 8.1 Hz, 1H),
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8.23 (s, 1H), 7.87 (d, J = 7.9 Hz, 1H), 7.50 – 7.42 (m, 2H), 1.61 (s, 9H). C NMR (101
MHz, CDCl3) δ 141.0 (s), 135.7 (s), 134.8 (s), 132.9 (s), 132.7 (s), 126.0 (s), 125.9 (s),
125.7 (s), 122.6 (s), 111.9 (s), 58.6 (s), 29.6 (s). IR (KBr): ν 2984, 2971, 2919, 2845, 2219,
1614, 1587, 1460, 1361, 1189, 892, 769 cm-1. HRMS (CI): m/z calcd for C14H15N2S [M+H]+,
243.0956 ; found, 243.0961.
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N-(tert-Butyl)cinnamimidoyl cyanide (2z). Yellow oil (47mg,44% yield). H NMR (400
MHz, CDCl3) δ 7.52 (dd, J = 7.5, 1.6 Hz, 2H), 7.40 (t, J = 11.9 Hz, 4H), 6.93 (d, J = 16.4
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Hz, 1H), 1.49 (s, 9H). C NMR (101 MHz, CDCl3) δ 141.1 (s), 138.2 (s), 134.9 (s), 130.1
(s), 129.1 (s), 128.5 (s), 127.9 (s), 111.2 (s), 58.6 (s), 29.6 (s). IR (KBr): ν 2970, 2927, 2855,
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2218, 1704, 1626, 1580, 1449, 1364, 1192, 966, 753, 691 cm-1. HRMS (CI): m/z calcd for
C14H17N2 [M+H]+, 213.1392 ; found, 213.1396.
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N-(2,4,4-Trimethylpentan-2-yl)-[1,1'-biphenyl]-4-carbimidoyl cyanide (3d). Colorless oil
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(113mg,71%yield). H NMR (400 MHz, CDCl3) δ 8.08 (d, J = 8.3 Hz, 2H), 7.67 (dd, J =
23.1, 8.1 Hz, 4H), 7.45 (dt, J = 14.6, 7.8 Hz, 3H), 1.94 (s, 2H), 1.62 (s, 6H), 1.04 (s, 9H).
13C NMR (101 MHz, CDCl3) δ 144.4 (s), 140.1 (s), 135.2 (s), 134.6 (s), 129.1 (s), 128.2 (s),
127.8 (s), 127.4 (d, J = 19.7 Hz), 112.2 (s), 62.5 (s), 56.6 (s), 32.0 (s), 29.6 (s). IR (KBr): ν
2952, 2869, 2212, 1596, 1485, 1365, 1214, 1003, 846, 766, 729, 695 cm-1. HRMS (CI): m/z
calcd for C22H27N2 [M+H]+, 319.2174 ; found, 319.2169.
3-Phenylquinoxalin-2-amine (4a).18e Yellow solid(68 mg, 77%yield). Mp: 181-183oC .1H
NMR (400 MHz, CDCl3) δ 7.97 (d, J = 8.2 Hz, 1H), 7.78 (d, J = 6.8 Hz, 2H), 7.70 (d, J =
8.3 Hz, 1H), 7.62 (d, J = 8.1 Hz, 1H), 7.54 (d, J = 7.4 Hz, 2H), 7.45 (t, J = 7.0 Hz, 2H), 5.17
13
(s, 2H). C NMR (101 MHz, CDCl3) δ 150.6 (s), 146.0 (s), 141.3 (s), 138.2 (s), 137.1 (s),
130.2 (s), 129.9 (s), 129.4 (s), 129.2 (s), 128.5 (s), 125.7 (s), 125.5 (s). HRMS (CI): m/z
calcd for C14H12N3 [M+H]+, 222.1031 ; found, 222.1035.
4-Methoxy-benzonitrile (2oa).6d White solid(29 mg, 74%yield). Mp: 62-63oC. H NMR
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(400 MHz, CDCl3) δ 7.55 (d, J = 5.1 Hz, 1H), 6.93 (d, J = 5.2 Hz, 1H), 3.83 (s, 2H). C
NMR (101 MHz, CDCl3) δ 162.9 (s), 134.0 (s), 119.2 (s), 114.8 (s), 103.9 (s), 55.6 (s).
HRMS (CI): m/z calcd for C8H8NO [M+H]+, 134.0606; found, 134.0604.
ASSOCIATED CONTENT
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Supporting Information Figures giving H and C NMR spectra. This material is available
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free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.5b01758.
AUTHOR INFORMATION
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Corresponding Authors
*(Yong-Ming Zhu) E-mail: zhuyongming@suda.edu.cn; fax: (+86)-512-67166591.
*(Jing-Kang Shen) E-mail: jkshen@mail.shcnc.ac.cn .
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
We gratefully acknowledge the financial support by PAPD (A Project Funded by the
Priority Academic Program Development of Jiangsu Higher Education Institutions).
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