4,5-Dioxo-imidazolinium Cation Activation of 1-Acyl-1-carbamoyl Oximes: Access to Cyanoformamides Using Dichloroimidazolidinedione

Article abstract of DOI:10.1021/acs.joc.9b02992

Cyanoformamides are prevalent as versatile building blocks for accessing synthetically useful intermediates and biologically active compounds. The development of a milder, simpler, and more efficient approach to cyanoformamides is nontrivial. Herein, we demonstrate the effectiveness of 4,5-dioxo-imidazolinium cation activation for transforming 1-acyl-1-carbamoyl oximes to cyanoformamides. By making use of the readily available and highly modifiable dichloroimidazolidinediones (DCIDs), this novel method of activation offers reactivity remarkably greater than that of other reported protocols, exhibits a high functional group compatibility with mild conditions, and could be scaled up easily. More than 30 examples are demonstrated with good to excellent yields in short reaction times. This research not only provides a mild and efficient alternative approach to assembling a portfolio of cyanoformamides but also extends the dichloroimidazolidinedione-mediated chemistry to encompass the C-C bond cleavage reaction.

Full text of DOI:10.1021/acs.joc.9b02992

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Article
4,5-Dioxo-imidazolinium Cation Activation of 1-Acyl-1-carbamoyl
Oximes: Access to Cyanoformamides Using Dichloroimidazolidinedione
Yu Gao, Zhihao Zhang, Zhenjiang Li, Tianfo Guo, Yuejia
Zhu, Zhiwei Yao, Bo Liu, Yongqiang Li, and Kai Guo
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b02992 • Publication Date (Web): 17 Dec 2019
Downloaded from pubs.acs.org on December 18, 2019
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4,5-Dioxo-imidazolinium Cation Activation of 1-Acyl-1-carbamoyl
Oximes: Access to Cyanoformamides Using Dichloroimidazolidinedione
Yu Gao,† Zhihao Zhang,† Zhenjiang Li,*,†,‡ Tianfo Guo,† Yuejia Zhu,† Zhiwei Yao,† Bo Liu,† Yongqiang
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Li,† and Kai Guo*,†,‡
†College of Biotechnology and Pharmaceutical Engineering, Nanjing Tech University, 30 Puzhu Road
South, Nanjing 211816, P. R. China
‡State Key Laboratory of Materials-Oriented Chemical Engineering, Nanjing Tech University, 30
Puzhu Road South, Nanjing 211816, P. R. China
ABSTRACT
Cyanoformamides are prevalent as versatile building blocks for accessing synthetically useful
intermediates and biologically active compounds. The development of a milder, simpler, and more
efficient approach to cyanoformamides is nontrivial. Herein, we demonstrate the effectiveness of
4,5-dioxo-imidazolinium cation activation for transforming 1-acyl-1-carbamoyl oximes to
cyanoformamides. By making use of the readily available and highly modifiable
dichloroimidazolidinediones (DCIDs), this novel method of activation offers reactivity remarkably
greater than that of other reported protocols, exhibits a high functional group compatibility with
the mild conditions, and could be scaled up easily. More than 30 examples are demonstrated with
good to excellent yields in short reaction times. This research not only provides a mild and efficient
alternative approach to assembling a portfolio of cyanoformamides, but also extends the
dichloroimidazolidinedione-mediated chemistry to encompass the C−C bond cleavage reaction.
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INTRODUCTION
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Cyanoformamides are a class of versatile building blocks for assembling synthetically useful
intermediates1 and biologically active compounds.2 A prototype cyanoformamide (NCCONH2) is a
known interstellar molecular precursor to nucleic acids under prebiotic conditions.3 In addition,
such a prevalent motif also exists in natural products, including antifouling ceratinamine,4
7-hydroxyceratinamine,5 subereamide A,6 and 12-hydroxysubereamide C (Scheme 1).6 Therefore,
considerable efforts have been made to develop methods for preparing valuable cyanoformamides.
Traditional methods focused on the cyanocarbonylation of amines with reagents such as carbonyl
cyanide,7 4-chloro-5H-1,2,3-dithiazol-5-one,8 triphosgene followed by substitution with a cyanide
ion,7b and isonitroso Meldrum’s acid9 or its tosyl derivatives.10 Yet, the use of highly toxic and
structurally complex reagents hampered their synthetic applications. Until recently, sporadic
examples of alternative approaches to cyanoformamides formation were reported.11 While
effective, most of these protocols called for elevated temperatures (60−140 °C)11b,d−f as well as long
reaction times11d,f or suffered from limited product scope excluding secondary
cyanoformamides.11c,d,f Worthy of note, Dong and co-workers reported a new pathway for the
synthesis of cyanoformamides from readily accessible 1-acyl-1-carbamoyl oximes mediated by
phosphoryltrichloride (POCl3).11b However, the reagent employed (POCl3) is hazardous and lacks the
ability of structural modification for the goal of enhancing reactivity. For these reasons, the
development of a novel alternative method aiming at mild reaction conditions, high efficiency,
broad substrate scope, and avoiding the use of undesirable reagents is still in high demand.
Scheme 1. Examples of Cyanoformamide-Containing Natural Products
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Recently, we have successfully demonstrated the great potential of 4,5-dioxo-imidazolinium
cation activation strategy in the Beckmann rearrangement using dichloroimidazolidinediones on a
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substoichiometric scale.12 2,2-Dichloroimidazolidine-4,5-diones (DCIDs) (1),13
a
planar
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five-membered N-heterocycle, possess a unique combination of stability of the oxalamide
framework and highly electrophilic reactivity of a quaternary germinal dichlorocarbon nucleus
(Scheme 2).14 Easy to prepare in nearly quantitative yield on a large scale,15 DCIDs are also highly
amenable to electronic and steric tunability. Besides, DCIDs bearing germinal halogens as good
leaving groups can dissociate to form 4,5-dioxo-imidazolinium chloride salts (A) (Scheme 2).16a
Despite having been known for over a half century, the synthetic value of DCIDs has only recently
been explored in a limited context.12,16 Particularly, DCIDs have rarely been utilized in mediating
C−C bond cleavage reaction.12
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Scheme 2. Proposed Design for 4,5-Dioxo-imidazolinium Cation Activation of 1-Acyl-1-carbamoyl
Oximes to Form Cyanoformamides
Inspired by the intriguing property of DCIDs, we envisioned that our recently developed
4,5-dioxo-imidazolinium cation system might also be capable of facilitating the conversion of
1-acyl-1-carbamoyl oximes to cyanoformamides (Scheme 2). Specifically, we assumed that
treatment of a 1-acyl-1-carbamoyl oxime 2 with a dichloroimidazolidinedione 1 would produce a
4,5-dioxo-imidazolinium oxime intermediate C, which would then be highly activated to furnish the
product cyanoformamide 3 along with imidazolidinetrione17 4. As a result, we advanced the
4,5-dioxo-imidazolinium cation activation strategy to the context of rapid transformation of
1-acyl-1-carbamoyl oximes to cyanoformamides via a C−C bond cleavage, offering a powerful
alternative method for accessing cyanoformamides with reactivity remarkably greater than that of
established protocols. Herein, we would like to report the development of such a mild and highly
efficient protocol.
RESUITS AND DISCUSSION
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We set out to test the possibility of 4,5-dioxo-imidazolinium-activated transformation of
2-(hydroxyimino)-3-oxo-N-phenylbutanamide (2a) as a model substrate. Our initial trial on the
conversion of 2a using 1.05 equiv of readily available DCID 1a in acetonitrile (MeCN) at room
temperature was promising (Table 1, entry 1). The target product phenylcarbamoyl cyanide (3a)
was obtained and imidazolidinetrione 4 was also observed. We next surveyed the effect of the
dichloroimidazolidinedione structure on reaction efficiency. Yield was significantly improved by
switching to N-alkyl substituents compared to that of DCID 1a with sterically demanding aryl groups
(entries 2–4). Remarkably, N-cyclohexyl substituted DCID 1d showcased superior reactivity,
affording cyanoformamide 3a in 89% yield in 30 min at room temperature (entry 4). This is
rationalized probably by the greater inclination for DCID 1d to ionize to produce the more sable
4,5-dioxo-imidazolinium carbocation, thereby facilitating the formation of the key
4,5-dioxo-imidazolinium oxime intermediate. The basis for the reactivity difference between DCID
1b and 1d in comparison to DCID 1c is unknown. This favorable result demonstrates that
4,5-dioxo-imidazolinium cation activation is a strategically viable means to promote this
transformation.
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A screening of the solvent effect revealed that other polar aprotic or nonpolar solvents,
including
dichloromethane (DCM), 1,2-dichloroethane (DCE), N,N-dimethylformamide (DMF),
dimethyl sulfoxide (DMSO), tetrahydrofuran (THF), and toluene, were less effective than MeCN
(Table 1, entry 4 vs entries 5–10). In the cases of entries 7–10, these media could only give the
target product in negligible yields (<5%), indicating that MeCN might serve as a critical and effective
medium for DCID 1d to ionize. Whereas a potential equivalent of HCl was generated in the course
of the reaction, treatment of 2a with 1.05 equiv of HCl in MeCN did not give any desired product,
excluding the possibility that the activation was owing to a background reaction (entry 11). On the
other hand, elevating the temperature affected little on the outcome of reaction (entries 12–14).
When using 1.5 equiv of DCID 1d, the yield increased up to 96% within 15 min (entry 16). Notably,
an essentially identical high yield (95%) was achieved after 15 min using only 1.2 equiv of DCID 1d
(entry 15). For comparison, POCl3 (1.5 equiv) in DCE solvent has been reported to demand 80 °C and
2 h to reach 83% product yield with this substrate.11b The notable advantages of our protocol, with
up to 8-fold decrease in the reaction duration, ambient temperature, and a higher yield, are more
desirable for sustainable and green synthesis.
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Table 1. Optimization of the Reaction Conditionsa
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entry reagent (equiv)
solvent
MeCN
MeCN
MeCN
MeCN
DCM
DCE
DMF
DMSO
THF
toluene
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MeCN
MeCN
MeCN
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MeCN
T (°C)
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time (min)
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yield (%)b
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1a (1.05)
1b (1.05)
1c (1.05)
1d (1.05)
1d (1.05)
1d (1.05)
1d (1.05)
1d (1.05)
1d (1.05)
1d (1.05)
HCl (1.05)
1d (1.05)
1d (1.05)
1d (1.05)
1d (1.2)
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<5
trace
trace
<5
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1d (1.5)
aReaction conditions: 2a (0.5 mmol), reagent, dry solvent (2.5 mL) under argon
atmosphere. bYield based on the substrate 2a. cHCl (36–38 wt%, 1.05 equiv,
0.525 mmol) was added.
With the optimized reaction conditions in hand, the generality of this protocol was
subsequently evaluated. In general, a variety of 1-acyl-1-carbamoyl oximes bearing either
secondary or tertiary amide groups were converted to their corresponding cyanoformamides in a
mild, rapid, and efficient fashion (Scheme 3). A gamut of functional groups, encompassing halides
(2f–2h, and 2m), ester (2i), ketone (2j), alkyne (2p), and boronic ester (2q), were well compatible
under the mild reaction conditions (Scheme 3A). 1-Acyl-1-carbamoyl oximes 2b–2j bearing either
electron-donating (2b–2d) or -withdrawing (2e–2j) groups at the para-position of the N-aryl ring
were accommodated, rapidly affording the desired cyanoformamides 3b–3j in good to excellent
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yields. In particular, it is noteworthy that 1-acyl-1-carbamoyl oxime 2e bearing a strong
electron-withdrawing group, namely, CF3, produces cyanoformamide 3e in 90% yield within 20 min
at room temperature. For comparison, the reagent POCl3 has been reported to require 80 °C to
reach 67% yield with this substrate.11b The position of the substituents on the N-aryl ring had a
minimal influence on the efficiency of this 4,5-dioxo-imidazolinium-activated transformation, as the
substrates (2l, 2o, and 2c) with ortho-, meta-, or para-substitution furnished the corresponding
cyanoformamides in comparably high yields. Also, steric hindrance did not restrain
cyanoformamides formation under this protocol, with ortho-, di-, and tris-substituted arenes (2l, 2r,
and 2s) also giving access to the desired products in high yields (92–93%) within a short time (10–30
min). Worthy of note, the presence of bromide and pinacol boronate in the cyanoformamides 3h
and 3q are synthetically valuable, which offers a platform for late-stage elaboration of the products
through cross-coupling reactions. Besides the N-phenyl-substituted 1-acyl-1-carbamoyl oximes,
substrates bearing biphenyl, naphthyl, and indanyl groups (2k, 2t, and 2u) could similarly engage
efficiently in the 4,5-dioxo-imidazolinium-activated transformation, yielding products 3k, 3t, and 3u
in good yields, respectively. In addition, N-alkyl-substituted 1-acyl-1-carbamoyl oximes 2v–2aa,
either N-benzyl, N-phenethyl, or N-phenylpropyl variations, also proved to be viable for the rapid
and efficient assembly of 3v–3aa by treatment of 1.5 equiv of 1d in MeCN at room temperature. In
the case of 2z containing a thiophene core in the aliphatic chain, the resulting product 3z was
obtained in 90% yield after 15 min.
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As expected, when the dioxime 2ab was subjected to this reaction using 3 equiv of 1d, the
dicarbamoyl cyanide 3ab was obtained in 95% yield (Scheme 3B). Furthermore, less active
1-acyl-1-carbamoyl oximes 2ac–2ae bearing tertiary amide groups in this protocol were found to
undergo efficient transformation, albeit a higher reaction temperature was entailed in these cases
(Scheme 3C). Other than methyl, additional variations in the R3 moiety of the 1-acyl-1-carbamoyl
oximes, such as ethyl (2ah), isopropyl (2ai), and phenyl (2aj), were surveyed (Scheme 3D). Whereas
1-acyl-1-carbamoyl oximes 2ah and 2ai afforded 3a in similar high yields within a short time,
substrate 2aj furnished 3a in only 33% yield. We hypothesize that this relatively poor result may be
due to the larger conjugated system of 2aj, which would make itself more stable and thus weaken
its ability to form the key 4,5-dioxo-imidazolinium oxime intermediate.
Scheme 3. Substrate Scope Studies for Cyanoformamides Formation via 4,5-Dioxo-imidazolinium
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Cation Activationa
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aReaction conditions: substrate 2 (0.5 mmol), 1d (1.2 equiv), and dry MeCN (2.5 mL) at 25 °C under
b
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Ar atmosphere. Yields based on 2 are given. 1d (1.5 equiv) was used. Dry DCM (2.5 mL) was used
as the solvent. dWith 3 equiv of 1d in dry MeCN (5.0 mL) for 2ab. eReaction performed at 80 °C with
1.2 equiv of 1d in dry MeCN (2.5 mL).
The synthesis of 1-acyl-1-carbamoyl oximes bearing primary amide groups could not be
achieved.18 The corresponding product (NCCONH2) was reported to be rather unstable at room
temperature and atmospheric pressure.3 N-heteroaryl-substituted 1-acyl-1-carbamoyl oximes 2af
and 2ag were also investigated (Scheme 3C). Although 1-acyl-1-carbamoyl oxime 2af bearing a
thiophene core reacted efficiently at elevated temperature, substrate 2ag with a basic quinoline
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ring was not compatible in this protocol.
Scheme 4. Scalability and Synthetic Applicationsa
aSee EXPERIMENTAL SECTION for detailed reaction conditions. TBAF=tetrabutylammonium fluoride.
To demonstrate the application potential of this method, the conversion of 1a was performed
on a one gram scale (Scheme 4a). An excellent product yield (94% yield) and a high efficiency (15
min) were still achieved. On the other hand, the thus obtained cyanoformamide product 3a could
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be further transformed into valuable building blocks (Scheme 4b). Treatment of 3a with (Boc)2O in a
NaBH4−CoCl2·6H2O reductive system readily afforded N-Boc carbamate 5 in 91% yield.19
Tetrazole-5-carboxamide 6 could be generated in 87% yield via dibutyltin oxide-mediated [3 + 2]
cycloaddition of cyanoformamide 3a with trimethylsilyl azide.20 In addition, cyanoformamide 3a
was easily converted to 1,2,4-oxadiazole derivative 7 (56% overall yield) via a tandem process of
amidoximation by hydroxylamine, acylation with benzoyl chloride, and cyclization with
tetrabutylammonium fluoride (TBAF) in a facile one-pot procedure. It is important to note that the
tetrazole skeleton 6 and 1,2,4-oxadiazole skeleton 7 are privileged motifs for a portfolio of
biologically active compounds, such as VEGFR-2 receptor inhibitor (8),21 anti-allergy compound
(9),2a antibacterial compound (10),22 and R1P1 kinase inhibitor (11)23 (Scheme 4c).
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Based on the above experimental results and our previous work,12 a tentative mechanism for
4,5-dioxo-imidazolinium-promoted reaction of 2 is depicted in Scheme 5. DCID 1 may exist in
equilibrium with 4,5-dioxo-imidazolinium chloride salt A,16a resulting in a rapid combination with
oxime substrate 2 to afford intermediate B. Subsequently, the neutral intermediate B re-ionizes via
dissociation of the second chlorine atom, giving the 4,5-dioxo-imidazolinium cation activated
intermediate C. Finally, concomitant C(sp2)-C(sp2) bond and N-O bond cleavages of intermediate C,
enabled by the attack of a chloride ion on the C=O double bond of intermediate C,11b could furnish
the cyanoformamide product 3 along with the imidazolidinetrione 4. Compound 4 was isolated and
characterized by NMR and HRMS. The formation of the acid chloride was also verified
experimentally (See EXPERIMENTAL SECTION for details).24
Scheme 5. Tentative Mechanism for 4,5-Dioxo-imidazolinium-Activated Reaction of 2
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CONCLUSION
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In conclusion, we have demonstrated the effectiveness of 4,5-dioxo-imidazolinium cation
activation for converting an array of 1-acyl-1-carbamoyl oximes to cyanoformamides under very
mild reaction conditions. Based on the readily accessible, electronically and sterically tunable
DCIDs, this novel protocol of activation offers reactivity that far surpasses other reported methods,
exhibits a broad functional group compatibility, and could be scaled up easily. This work not only
provides a highly efficient alternative approach to assembling cyanoformamides, but also enriches
and diversifies the dichloroimidazolidinedione-mediated chemistry that includes the C−C bond
cleavage reaction.
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EXPERIMENTAL SECTION
General Information. Reactions, unless otherwise noted, were performed with magnetic stirring
in oven-dried glassware. All reagents were used as received without being further purified.
Reaction solvents were distilled according to standard laboratory methods prior to use. Analytical
thin-layer chromatography (TLC) was carried out on precoated silica gel plates (HSGF 254) and
visualized under UV irradiation (254 nm). Flash column chromatography was performed using silica
gel (200−300 mesh).
13
1H and C NMR spectra were recorded in CDCl3 or DMSO-d6 on a Bruker Avance 400 and 100
MHz NMR spectrometer. Chemical shifts (δ) are reported in parts per million (ppm) relative to
13
residual solvent peak (1H δ 7.26 for CDCl3, δ 2.50 for DMSO-d6; C δ 77.16 for CDCl3, δ 39.52 for
DMSO-d6). The following abbreviations were used to explain NMR peak multiplicities: brs = broad
signal, s = singlet, d = doublet, t = triplet, q = quartet, p = pentet, sept = septet, and m = multiplet.
High-resolution mass spectra (HRMS) were obtained on an Agilent Technologies 6520 Q-TOF LC/MS
mass spectrometer with an electron spray ionization (ESI) probe or an Agilent Technologies 7250
GC/Q-TOF mass spectrometer with an electron impact ionization (EI) probe. Melting points were
measured using a capillary melting point apparatus (Shanghai Precision & Scientific Instrument Co.,
LTD) in degrees Celsius (°C).
The starting material 1-acyl-1-carbamoyl oximes 2a−2aj were prepared according to the reported
procedures18 on a 8 mmol scale. Dichloroimidazolidinediones 1a−1d were prepared according to
our previous work.12
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New Starting Materials. N-([1,1'-Biphenyl]-4-yl)-2-(hydroxyimino)-3-oxobutanamide (2k). A
yellow solid, 1.81 g, 80% yield. Rf = 0.47 (petroleum ether (PE)/ethyl acetate (EA), 2:1); mp
179.1−180.6 °C; 1H NMR (400 MHz, DMSO-d6) δ 12.93 (s, 1H), 10.48 (s, 1H), 7.70−7.64 (m, 6H), 7.45
(t, J = 7.4 Hz, 2H), 7.35−7.32 (m, 1H), 2.38 (s, 3H); 13C{1H} NMR (100 MHz, DMSO-d6) δ 194.5, 160.0,
153.3, 139.6, 137.7, 135.5, 128.9, 127.2, 127.1, 126.3, 119.5, 25.3; HRMS (ESI-TOF) m/z [M + Na]+
calcd for C16H14N2O3Na 305.0897, found 305.0890.
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2-(Hydroxyimino)-3-oxo-N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)butanamide
(2q). A colorless solid, 2.07 g, 78% yield. Rf = 0.46 (PE/EA, 2:1); mp 149.1−150.0 °C; 1H NMR (400
MHz, CDCl3) δ 11.04 (brs, 1H), 7.82 (d, J = 8.0 Hz, 2H), 7.60 (d, J = 8.0 Hz, 2H), 2.58 (s, 3H), 1.35 (s,
12H); 13C{1H} NMR (100 MHz, CDCl3) δ 200.3, 161.6, 143.6, 138.1, 136.0, 120.5, 84.1, 26.6, 25.0 (The
carbon directly attached to the boron atom was not detected due to quadrupolar broadening.);
HRMS (ESI-TOF) m/z [M + Na]+ calcd for C16H21BN2O5Na 355.1444, found 355.1446.
N-(2,3-Dihydro-1H-inden-1-yl)-2-(hydroxyimino)-3-oxobutanamide (2u). A colorless solid, 1.64 g,
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83% yield. Rf = 0.48 (PE/EA, 3:1); mp 134.2−135.1 °C; H NMR (400 MHz, CDCl3) δ 9.20 (brs, 1H),
7.23−7.14 (m, 4H), 5.44 (q, J = 7.6 Hz, 1H), 3.03−2.96 (m, 1H), 2.90−2.82 (m, 1H), 2.61−2.53 (m, 1H),
2.43 (s, 3H), 1.92−1.83 (m, 1H); 13C{1H} NMR (100 MHz, CDCl3) δ 199.6, 163.5, 143.6, 143.4, 141.6,
128.6, 127.2, 125.1, 124.2, 54.3, 33.5, 30.5, 26.4; HRMS (ESI-TOF) m/z [M + Na]+ calcd for
C13H14N2O3Na 269.0897, found 269.0901.
2-(Hydroxyimino)-3-oxo-N-(2-(thiophen-2-yl)ethyl)butanamide (2z). A pale yellow solid, 1.52 g,
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79% yield. Rf = 0.42 (PE/EA, 4:1); mp 69.0−71.1 °C; H NMR (400 MHz, CDCl3) δ 9.13 (brs, 1H), 7.19
(dd, J = 5.1, 1.2 Hz, 1H), 6.97 (dd, J = 5.1, 3.5 Hz, 1H), 6.89−6.88 (m, 1H), 3.67−3.62 (m, 2H), 3.12 (t, J
= 6.8 Hz, 2H), 2.49 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 199.6, 163.8, 143.5, 140.2, 127.3, 125.8,
124.5, 40.4, 29.3, 26.4; HRMS (ESI-TOF) m/z [M + Na]+ calcd for C10H12N2O3SNa 263.0461, found
263.0469.
2-(Hydroxyimino)-3-oxo-N-(3-phenylpropyl)butanamide (2aa). A colorless solid, 1.25 g, 83% yield.
Rf = 0.53 (PE/EA, 4:1); mp 124.0−124.2 °C; 1H NMR (400 MHz, DMSO-d6) δ 12.64 (s, 1H), 8.27 (t, J =
5.4 Hz, 1H), 7.30−7.26 (m, 2H), 7.21−7.15 (m, 3H), 3.13 (q, J = 6.6 Hz, 2H), 2.62−2.59 (m, 2H), 2.31 (s,
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3H), 1.74−1.67 (m, 2H); C{1H} NMR (100 MHz, DMSO-d6) δ 194.4, 161.2, 154.0, 141.8, 128.4,
128.3, 125.7, 37.7, 32.2, 30.9, 25.3; HRMS (ESI-TOF) m/z [M + Na]+ calcd for C13H16N2O3Na
271.1053, found 271.1056.
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N,N'-(1,4-Phenylene)bis(2-(hydroxyimino)-3-oxobutanamide) (2ab). A yellow solid, 2.01 g, 75%
yield. Rf = 0.45 (PE/EA, 1:2); mp 192.3−193.3 °C; 1H NMR (400 MHz, DMSO-d6) δ 12.87 (s, 2H), 10.34
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(s, 2H), 7.55 (s, 4H), 2.36 (s, 6H); C{1H} NMR (100 MHz, DMSO-d6) δ 194.5, 159.7, 153.3, 134.2,
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119.6, 25.3; HRMS (ESI-TOF) m/z [M + Na]+ calcd for C14H14N4O6Na 357.0806, found 357.0815.
Methyl 2-(2-(Hydroxyimino)-3-oxobutanamido)thiophene-3-carboxylate (2af). A yellow solid, 1.10
g, 51% yield. Rf = 0.40 (DCM); mp 152.1−153.0 °C; 1H NMR (400 MHz, CDCl3) δ 13.39 (brs, 1H), 7.33
(d, J = 5.7 Hz, 1H), 6.95 (d, J = 5.7 Hz, 1H), 3.98 (s, 3H), 2.59 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ
198.7, 164.6, 159.3, 143.6, 142.8, 125.3, 119.4, 117.3, 52.4, 26.3; HRMS (ESI-TOF) m/z [M + Na]+
calcd for C10H10N2O5SNa 293.0203, found 293.0209.
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2-(Hydroxyimino)-3-oxo-N-(quinolin-8-yl)butanamide (2ag). A light yellow solid, 0.86 g, 42% yield.
Rf = 0.45 (DCM); mp 161.4−162.7 °C;1H NMR (400 MHz, CDCl3) δ 12.76 (brs, 1H), 8.92−8.91 (m, 1H),
8.62 (d, J = 7.6 Hz, 1H), 8.11−8.09 (m, 1H), 7.55 (d, J = 8.2 Hz, 1H), 7.48−7.41 (m, 2H), 2.54 (s, 3H);
13C{1H} NMR (100 MHz, CDCl3) δ 199.3, 161.6, 149.6, 144.1, 139.6, 136.4, 133.1, 128.2, 127.0, 124.4,
122.1, 119.4, 26.6; HRMS (ESI-TOF) m/z [M + H]+ calcd for C13H12N3O3 258.0873, found 258.0877.
2-(Hydroxyimino)-3-oxo-N-phenylpentanamide (2ah). A colorless solid, 1.43 g, 81% yield. Rf = 0.50
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(PE/EA, 3:1); mp 81.1−81.8 °C; H NMR (400 MHz, CDCl3) δ 11.06 (brs, 1H), 7.60 (d, J = 7.6 Hz, 2H),
7.39 (t, J = 8.0 Hz, 2H), 7.23 (t, J = 7.4 Hz, 1H), 3.04 (q, J = 7.2 Hz, 2H), 1.18 (t, J = 7.2 Hz, 3H); 13C{1H}
NMR (100 MHz, CDCl3) δ 203.0, 161.6, 143.0, 135.6, 129.4, 126.4, 121.5, 31.7, 8.1; HRMS (ESI-TOF)
m/z [M + Na]+ calcd for C11H12N2O3Na 243.0740, found 243.0738.
2-(Hydroxyimino)-4-methyl-3-oxo-N-phenylpentanamide (2ai). A colorless solid, 1.61 g, 86% yield.
Rf = 0.59 (PE/EA, 3:1); mp 97.4−99.6 °C; 1H NMR (400 MHz, CDCl3) δ 11.13 (brs, 1H), 7.60 (d, J = 7.6
Hz, 2H), 7.39 (t, J = 8.0 Hz, 2H), 7.23 (t, J = 7.6 Hz, 1H), 3.84 (sept, J = 6.9 Hz, 1H), 1.20 (d, J = 6.8 Hz,
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6H); C{1H} (100 MHz, CDCl3) δ 206.5, 161.9, 141.8, 135.5, 129.4, 126.3, 121.5, 35.2, 19.1; HRMS
(ESI-TOF) m/z [M + Na]+ calcd for C12H14N2O3Na 257.0897, found 257.0915.
2-(Hydroxyimino)-3-oxo-N,3-diphenylpropanamide (2aj). A colorless solid, 1.70 g, 79% yield. Rf =
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0.60 (PE/EA, 1:1); mp 179.2−180.3 °C; H NMR (400 MHz, DMSO-d6) δ 12.57 (brs, 1H), 10.36 (brs,
1H), 7.86 (d, J = 7.9 Hz, 2H), 7.75−7.76 (m, 3H), 7.61 (t, J = 7.6 Hz, 2H), 7.33 (t, J = 7.8 Hz, 2H), 7.11 (t,
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J = 7.4 Hz, 1H); C{1H} (100 MHz, DMSO-d6) δ 192.3, 160.0, 150.8, 137.9, 134.7, 134.4, 129.3,
128.74, 128.73, 124.3, 120.5; HRMS (ESI-TOF) m/z [M + Na]+ calcd for C15H12N2O3Na 291.0740,
found 291.0741.
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General Procedure for the Synthesis of Cyanoformamides 3. The substrates 2a−2ah (0.5 mmol,
1.0 equiv), DCID 1d (200.0 mg, 0.6 mmol, 1.2 equiv), and anhydrous MeCN (2.5 mL) were
continuously added to a flame-dried Schlenk tube under an argon atmosphere. Then the reaction
mixture was stirred at 25 °C for 10 to 60 min, depending on the substrate. Upon completion of the
reaction (monitored by TLC), the organic solvent was evaporated under reduced pressure, and the
residue was purified via flash column chromatography to furnish the desired products 3a−3af.
Phenylcarbamoyl Cyanide (3a).11b The compound was prepared from 2a (103.1 mg, 0.5 mmol) by
following the general procedure. The reaction time was 15 min. Purification by flash column
chromatography (PE/EA, 40:1 to 20:1) furnished 3a (69.4 mg, 95% yield) as a colorless solid: Rf =
0.54 (PE/EA, 3:1); mp 124.5−125.8 °C; 1H NMR (400 MHz, DMSO-d6) δ 11.83 (brs, 1H), 7.57 (d, J =
7.6 Hz, 2H), 7.40 (t, J = 7.2 Hz, 2H), 7.24−7.19 (m, 1H); 13C{1H} (100 MHz, DMSO-d6) δ 140.7, 136.7,
129.3, 125.8, 120.3, 112.5.
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4-Tolylcarbamoyl Cyanide (3b).11b The compound was prepared from 2b (110.1 mg, 0.5 mmol) by
following the general procedure. The reaction time was 10 min. Purification by flash column
chromatography (PE/EA, 40:1 to 20:1) furnished 3b (76.9 mg, 96% yield) as a colorless solid: Rf =
0.55 (PE/EA, 3:1); mp 179.6−180.5 °C; 1H NMR (400 MHz, DMSO-d6) δ 11.75 (brs, 1H), 7.46 (d, J = 8.1
Hz, 2H), 7.20 (d, J = 8.0 Hz, 2H), 2.27 (s, 3H); 13C{1H} (100 MHz, DMSO-d6) δ 140.5, 135.1, 134.3,
129.6, 120.2, 112.6, 20.6.
(4-Methoxyphenyl)carbamoyl Cyanide (3c).11b The compound was prepared from 2c (118.1 mg,
0.5 mmol) by following the general procedure. The reaction time was 10 min. Purification by flash
column chromatography (PE/EA, 40:1 to 20:1) furnished 3c (81.0 mg, 92% yield) as a colorless solid:
Rf = 0.51 (PE/EA, 3:1); mp 146.1−147.8 °C; 1H NMR (400 MHz, DMSO-d6) δ 11.71 (brs, 1H), 7.50 (d, J
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= 8.4 Hz, 2H), 6.96 (d, J = 8.4 Hz, 2H), 3.74 (s, 3H); C{1H} (100 MHz, DMSO-d6) δ 156.9, 140.3,
129.7, 121.8, 114.3, 112.7, 55.3.
(4-(tert-Butyl)phenyl)carbamoyl Cyanide (3d). The compound was prepared from 2d (131.2 mg,
0.5 mmol) by following the general procedure with the following exception: the reaction performed
using 1.5 equiv of 1d (249.9 mg, 0.75 mmol) in anhydrous DCM (2.5 mL). The reaction time was 40
min. Purification by flash column chromatography (PE/EA, 40:1 to 20:1) furnished 3d (94.0 mg, 93%
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yield) as a colorless solid: Rf = 0.56 (PE/EA, 5:1); mp 138.1−140.9 °C; H NMR (400 MHz, CDCl3) δ
7.94 (brs, 1H), 7.44−7.39 (m, 4H), 1.31 (s, 9H); 13C{1H} NMR (100 MHz, CDCl3) δ 150.2, 140.4, 132.8,
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126.5, 120.3, 111.9, 34.8, 31.4.
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(4-(Trifluoromethyl)phenyl)carbamoyl Cyanide (3e).11b The compound was prepared from 2e
(137.1 mg, 0.5 mmol) by following the general procedure. The reaction time was 20 min.
Purification by flash column chromatography (PE/EA, 40:1 to 15:1) furnished 3e (96.4 mg, 90%
yield) as a colorless solid: Rf = 0.57 (PE/EA, 3:1); mp 125.8−127.7 °C; 1H NMR (400 MHz, CDCl3) δ
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8.07 (s, 1H), 7.69−7.64 (m, 4H); 13C{1H} NMR (100 MHz, CDCl3) δ 140.5, 138.3, 128.9 (q, JCF = 33.2
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Hz), 127.0 (q, JCF = 3.7 Hz), 123.7 (q, JCF = 270.4 Hz), 120.4, 111.4; F NMR (376 MHz, CDCl3) δ
−62.5.
(4-Fluorophenyl)carbamoyl Cyanide (3f). The compound was prepared from 2f (142.6 mg, 0.5
mmol) by following the general procedure. The reaction time was 30 min. Purification by flash
column chromatography (PE/EA, 30:1 to 15:1) furnished 3f (66.5 mg, 81% yield) as a colorless solid:
Rf = 0.41 (PE/EA, 3:1); mp 117.4−119.7 °C; 1H NMR (400 MHz, CDCl3) δ 7.97 (brs, 1H), 7.51−7.48 (m,
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2H), 7.13−7.07 (m, 2H); 13C{1H} NMR (100 MHz, CDCl3) δ 160.8 (d, JCF = 246.3 Hz), 140.5, 131.4 (d,
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4JCF = 3.4 Hz), 122.5 (d, JCF = 8.1 Hz), 116.5 (d, JCF = 22.9 Hz), 111.7; F NMR (376 MHz, CDCl3) δ
−113.6.
(4-Chlorophenyl)carbamoyl Cyanide (3g).11b The compound was prepared from 2g (120.3 mg, 0.5
mmol) by following the general procedure. The reaction time was 30 min. Purification by flash
column chromatography (PE/EA, 30:1 to 20:1) furnished 3g (84.0 mg, 93% yield) as a colorless solid:
Rf = 0.39 (PE/EA, 3:1); mp 238.2−239.9 °C; 1H NMR (400 MHz, DMSO-d6) δ 11.95 (brs, 1H), 7.59 (d, J
= 8.9 Hz, 2H), 7.47 (d, J = 8.9 Hz, 2H); 13C{1H} NMR (100 MHz, DMSO-d6) δ 140.8, 135.6, 129.5, 129.2,
121.9, 112.4.
(4-Bromophenyl)carbamoyl Cyanide (3h). The compound was prepared from 2h (142.6 mg, 0.5
mmol) by following the general procedure with the following exception: the reaction performed
using 1.5 equiv of 1d (249.9 mg, 0.75 mmol). The reaction time was 15 min. Purification by flash
column chromatography (PE/EA, 30:1 to 20:1) furnished 3h (108.0 mg, 96% yield) as a light yellow
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solid: Rf = 0.66 (PE/EA, 3:1); mp 265.4−267.3 °C; H NMR (400 MHz, DMSO-d6) δ 11.93 (brs, 1H),
7.60 (d, J = 8.8 Hz, 2H), 7.53 (d, J = 8.8 Hz, 2H); 13C{1H} NMR (100 MHz, DMSO-d6) δ 140.7, 136.0,
132.1, 122.2, 117.7, 112.3.
Ethyl 4-((Cyanocarbonyl)amino)benzoate (3i). The compound was prepared from 2i (139.1 mg,
0.5 mmol) by following the general procedure with the following exception: the reaction performed
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using 1.5 equiv of 1d (249.9 mg, 0.75 mmol). The reaction time was 10 min. Purification by flash
column chromatography (PE/EA, 30:1 to 15:1) furnished 3i (103.7 mg, 95% yield) as a colorless
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solid: Rf = 0.45 (PE/EA, 3:1); mp 212.8−213.9 °C; H NMR (400 MHz, DMSO-d6) δ 12.12 (brs, 1H),
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7.99 (d, J = 8.8 Hz, 2H), 7.70 (d, J = 8.8 Hz, 2H), 4.30 (q, J = 7.2 Hz, 2H), 1.31 (t, J = 7.2 Hz, 3H); 13C{1H}
NMR (100 MHz, DMSO-d6) δ 165.0, 141.0, 140.8, 130.4, 126.6, 119.9, 112.3, 60.8, 14.2.
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(4-Acetylphenyl)carbamoyl Cyanide (3j). The compound was prepared from 2j (124.1 mg, 0.5
mmol) by following the general procedure. The reaction time was 10 min. Purification by flash
column chromatography (PE/EA, 40:1 to 10:1) furnished 3j (84.7 mg, 90% yield) as a yellow solid: Rf
= 0.50 (PE/EA, 2:1); mp 180.1−181.7 °C; 1H NMR (400 MHz, DMSO-d6) δ 12.09 (brs, 1H), 7.99 (d, J =
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8.8 Hz, 2H), 7.69 (d, J = 8.8 Hz, 2H), 2.55 (s, 3H); C{1H} NMR (100 MHz, DMSO-d6) δ 196.6, 141.0,
140.7, 133.7, 129.6, 119.8, 112.3, 26.5.
[1,1'-Biphenyl]-4-ylcarbamoyl Cyanide (3k). The compound was prepared from 2k (141.2 mg, 0.5
mmol) by following the general procedure with the following exception: the reaction performed
using 1.5 equiv of 1d (249.9 mg, 0.75 mmol) in anhydrous DCM (2.5 mL). The reaction time was 60
min. Purification by flash column chromatography (PE/EA, 30:1 to 20:1) furnished 3k (70.0 mg, 63%
yield) as a colorless solid: Rf = 0.54 (PE/EA, 3:1); mp 266.3−269.6 °C; 1H NMR (400 MHz, DMSO-d6) δ
11.91 (brs, 1H), 7.73−7.71 (m, 2H), 7.67−7.65 (m, 4H), 7.46 (t, J = 7.8 Hz, 2H), 7.38−7.34 (m, 1H);
13C{1H} NMR (100 MHz, DMSO-d6) δ 140.6, 139.2, 137.4, 136.0, 129.0, 127.5, 127.3, 126.5, 120.7,
112.5.
(2-Methoxyphenyl)carbamoyl Cyanide (3l).11b The compound was prepared from 2l (118.1 mg, 0.5
mmol) by following the general procedure. The reaction time was 30 min. Purification by flash
column chromatography (PE/EA, 30:1 to 15:1) furnished 3l (81.9 mg, 93% yield) as a colorless solid:
Rf = 0.50 (PE/EA, 3:1); mp 112.1−114.3 °C; 1H NMR (400 MHz, CDCl3) δ 8.38 (brs, 1H), 8.18 (dd, J =
8.1, 1.6 Hz, 1H), 7.21−7.17 (m, 1H), 7.01−6.97 (m, 1H), 6.95−6.93 (m, 1H), 3.94 (s, 3H); 13C{1H} NMR
(100 MHz, CDCl3) δ 148.0, 140.0, 126.7, 125.4, 121.4, 120.9, 111.9, 110.4, 56.0.
(3-Chlorophenyl)carbamoyl Cyanide (3m). The compound was prepared from 2m (120.3 mg, 0.5
mmol) by following the general procedure. The reaction time was 10 min. Purification by flash
column chromatography (PE/EA, 40:1 to 25:1) furnished 3m (84.0 mg, 93% yield) as a colorless
solid: Rf = 0.59 (PE/EA, 3:1); mp 118.5−120.5 °C; 1H NMR (400 MHz, DMSO-d6) δ 12.00 (brs, 1H),
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7.69 (t, J = 1.8 Hz, 1H), 7.49−7.42 (m, 2H), 7.29 (dt, J = 7.4, 1.8 Hz, 1H); C{1H} NMR (100 MHz,
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(3-Ethylphenyl)carbamoyl Cyanide (3n). The compound was prepared from 2n (117.1 mg, 0.5
mmol) by following the general procedure. The reaction time was 15 min. Purification by flash
column chromatography (PE/EA, 40:1 to 25:1) furnished 3n (73.2 mg, 84% yield) as a colorless solid:
Rf = 0.53 (PE/EA, 5:1); mp 107.9−110.1 °C; 1H NMR (400 MHz, CDCl3) δ 8.02 (brs, 1H), 7.34−7.28 (m,
3H), 7.11−7.08 (m, 1H), 2.66 (q, J = 7.6 Hz, 2H), 1.24 (t, J = 7.6 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3)
δ 146.1, 140.4, 135.5, 129.5, 126.5, 120.0, 117.9, 111.9, 28.9, 15.5; HRMS (EI-TOF) m/z [M − HCN]+
calcd for C9H9NO 147.0679, found 147.0679.
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(3-Methoxyphenyl)carbamoyl cyanide (3o). The compound was prepared from 2o (118.1 mg, 0.5
mmol) by following the general procedure. The reaction time was 10 min. Purification by flash
column chromatography (PE/EA, 30:1 to 15:1) furnished 3o (82.8 mg, 94% yield) as a colorless solid:
Rf = 0.46 (PE/EA, 3:1); mp 94.5−96.9 °C; 1H NMR (400 MHz, CDCl3) δ 8.10 (brs, 1H), 7.24–7.22 (m,
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1H), 7.14 (t, J = 2.4 Hz, 1H), 6.98−6.95 (m, 1H), 6.77−6.74 (m, 1H), 3.77 (s, 3H); C{1H} NMR (100
MHz, CDCl3) δ 159.2, 139.3, 135.4, 129.2, 111.45, 111.40, 110.6, 105.4, 54.4.
(3-Ethynylphenyl)carbamoyl Cyanide (3p). The compound was prepared from 2p (115.1 mg, 0.5
mmol) by following the general procedure. The reaction time was 15 min. Purification by flash
column chromatography (PE/EA, 40:1 to 20:1) furnished 3p (80.1 mg, 93% yield) as a colorless solid:
Rf = 0.53 (PE/EA, 3:1); mp 261.2−263.2 °C; 1H NMR (400 MHz, CDCl3) δ 7.81 (brs, 1H), 7.64−7.63 (m,
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1H), 7.52−7.49 (m, 1H), 7.38−7.35 (m, 2H), 3.13 (s, 1H); C{1H} NMR (100 MHz, CDCl3) δ 140.5,
135.5, 130.5, 129.7, 123.9, 123.7, 120.9, 111.6, 82.4, 78.8; HRMS (EI-TOF) m/z [M − HCN]+ calcd for
C9H5NO 143.0366, found 143.0363.
(4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)carbamoyl Cyanide (3q). The compound
was prepared from 2q (166.1 mg, 0.5 mmol) by following the general procedure. The reaction time
was 20 min. Purification by flash column chromatography (PE/EA, 40:1 to 20:1) furnished 3q (108.8
mg, 80% yield) as a colorless solid: Rf = 0.47 (PE/EA, 4:1); mp 167.4−168.3 °C; 1H NMR (400 MHz,
CDCl3) δ 7.99 (brs, 1H), 7.82 (d, J = 8.4 Hz, 2H), 7.50 (d, J = 8.4 Hz, 2H), 1.34 (s, 12H); 13C{1H} NMR
(100 MHz, CDCl3) δ 140.3, 137.9, 136.2, 119.4, 111.7, 84.2, 25.0 (The carbon directly attached to the
boron atom was not detected due to quadrupolar broadening.); HRMS (EI-TOF) m/z [M − HCN]+
calcd for C13H16BNO3 245.1218, found 245.1217.
(2,4-Dimethylphenyl)carbamoyl Cyanide (3r) .11b The compound was prepared from 2r (117.1 mg,
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0.5 mmol) by following the general procedure. The reaction time was 15 min. Purification by flash
column chromatography (PE/EA, 50:1 to 30:1) furnished 3r (80.1 mg, 92% yield) as a colorless solid:
Rf = 0.63 (PE/EA, 5:1); mp 86.3−88.2 °C; 1H NMR (400 MHz, DMSO-d6) δ 11.24 (brs, 1H), 7.23 (d, J =
8.0 Hz, 1H), 7.09 (s, 1H), 7.03 (d, J = 8.0 Hz, 1H), 2.26 (s, 3H), 2.17 (s, 3H); 13C{1H} NMR (100 MHz,
DMSO-d6) δ 141.7, 136.7, 132.4, 131.3, 130.7, 126.9, 125.4, 112.7, 20.6, 17.6.
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(4-Chloro-2,5-dimethoxyphenyl)carbamoyl Cyanide (3s).11b The compound was prepared from 2s
(150.4 mg, 0.5 mmol) by following the general procedure with the following exception: the reaction
performed using 1.5 equiv of 1d (249.9 mg, 0.75 mmol). The reaction time was 10 min. Purification
by flash column chromatography (PE/EA, 40:1 to 20:1) furnished 3s (110.7 mg, 92% yield) as a
colorless solid: Rf = 0.49 (PE/EA, 3:1); mp 142.7−144.5 °C; 1H NMR (400 MHz, CDCl3) δ 8.34 (brs, 1H),
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7.95 (s, 1H), 6.97 (s, 1H), 3.90 (s, 3H), 3.87 (s, 3H); C{1H} NMR (100 MHz, CDCl3) δ 149.3, 142.1,
139.9, 124.5, 119.3, 112.9, 111.6, 105.6, 57.0, 56.7.
Naphthalen-2-ylcarbamoyl Cyanide (3t). The compound was prepared from 2t (128.1 mg, 0.5
mmol) by following the general procedure with the following exception: the reaction performed
using 1.5 equiv of 1d (249.9 mg, 0.75 mmol). The reaction time was 10 min. Purification by flash
column chromatography (PE/EA, 40:1 to 25:1) furnished 3t (89.3 mg, 91% yield) as a light yellow
solid: Rf = 0.58 (PE/EA, 3:1); mp 248.1−250.0 °C; 1H NMR (400 MHz, DMSO-d6) δ 12.02 (brs, 1H),
8.24 (d, J = 2.0 Hz, 1H), 7.97−7.90 (m, 3H), 7.59 (dd, J = 8.8, 2.1 Hz, 1H), 7.55−7.48 (m, 2H); 13C{1H}
NMR (100 MHz, DMSO-d6) δ 140.8, 134.2, 132.9, 130.8, 129.0, 127.7, 127.6, 126.9, 125.9, 119.7,
117.5, 112.5.
(2,3-Dihydro-1H-inden-1-yl)carbamoyl Cyanide (3u). The compound was prepared from 2u (123.1
mg, 0.5 mmol) by following the general procedure. The reaction time was 15 min. Purification by
flash column chromatography (PE/EA, 40:1 to 25:1) furnished 3u (82.9 mg, 89% yield) as a colorless
solid: Rf = 0.50 (PE/EA, 6:1); mp 115.3−117.0 °C. A rotamerization of 3u was observed in NMR
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spectra. H NMR (400 MHz, CDCl3) (major rotamer) δ 7.22−7.13 (m, 4H), 6.51 (brs, 1H), 5.38−5.33
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(m, 1H), 2.99−2.91 (m, 1H), 2.86−2.78 (m, 1H), 2.55−2.47 (m, 1H), 1.88−1.79 (m, 1H); C{1H} NMR
(100 MHz, CDCl3) (major rotamer) δ 143.6, 142.9, 140.5, 129.1, 127.3, 125.3, 124.3, 111.6, 56.1,
33.3, 30.3; HRMS (EI-TOF) m/z [M − HCN]+ calcd for C10H9NO 159.0679, found 159.0676.
Benzylcarbamoyl Cyanide (3v).11b The compound was prepared from 2v (110.1 mg, 0.5 mmol) by
following the general procedure with the following exception: the reaction performed using 1.5
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equiv of 1d (249.9 mg, 0.75 mmol). The reaction time was 10 min. Purification by flash column
chromatography (PE/EA, 40:1 to 15:1) furnished 3v (71.3 mg, 89% yield) as a colorless solid: Rf =
0.48 (PE/EA, 3:1) ); mp 70.4−71.0 °C. A rotamerization of 3v was observed in NMR spectra (19:1
mixture of rotamers). 1H NMR (400 MHz, CDCl3) (major rotamer) δ 7.39−7.36 (m, 3H), 7.30−7.27 (m,
2H), 6.49 (brs, 1H), 4.51 (d, J = 6.0 Hz, 2H); 13C{1H} NMR (100 MHz, CDCl3) (major rotamer) δ 143.1,
135.2, 129.3, 128.7, 128.2, 111.5, 44.6.
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(4-Fluorophenethyl)carbamoyl Cyanide (3w). The compound was prepared from 2w (126.1 mg,
0.5 mmol) by following the general procedure with the following exception: the reaction performed
using 1.5 equiv of 1d (249.9 mg, 0.75 mmol). The reaction time was 15 min. Purification by flash
column chromatography (PE/EA, 40:1 to 15:1) furnished 3w (88.4 mg, 92% yield) as a colorless oil:
Rf = 0.48 (PE/EA, 3:1). A rotamerization of 3w was observed in NMR spectra (19:1 mixture of
rotamers). 1H NMR (400 MHz, CDCl3) (major rotamer) δ 7.17−7.13 (m, 2H), 7.03−6.99 (m, 2H), 6.90
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(brs, 1H), 3.56 (q, J = 6.0 Hz, 2H), 2.84 (t, J = 7.2 Hz, 2H); C{1H} NMR (100 MHz, CDCl3) (major
rotamer) δ 162.0 (d, 1JCF = 243.4 Hz) , 143.4, 133.1 (d, 4JCF = 3.0 Hz), 130.3 (d, 3JCF = 7.9 Hz), 115.8 (d,
2JCF = 20.9 Hz), 111.6, 41.7, 34.0; 19F NMR (376 MHz, CDCl3) (major rotamer) δ −115.6.
(4-Methylphenethyl)carbamoyl Cyanide (3x). The compound was prepared from 2x (124.1 mg, 0.5
mmol) by following the general procedure with the following exception: the reaction performed
using 1.5 equiv of 1d (249.9 mg, 0.75 mmol). The reaction time was 15 min. Purification by flash
column chromatography (PE/EA, 30:1 to 10:1) furnished 3x (87.5 mg, 93% yield) as a colorless oil: Rf
= 0.61 (PE/EA, 3:1). A rotamerization of 3x was observed in NMR spectra (19:1 mixture of
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rotamers). H NMR (400 MHz, CDCl3) (major rotamer) δ 7.16 (d, J = 8.0 Hz, 2H), 7.08 (d, J = 8.0 Hz,
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2H), 6.36 (brs, 1H), 3.59 (q, J = 6.0 Hz, 2H), 2.83 (t, J = 7.0 Hz, 2H), 2.35 (s, 3H); C{1H} NMR (100
MHz, CDCl3) (major rotamer) δ 143.2, 136.9, 134.1, 129.8, 128.6, 111.6, 41.7, 34.4, 21.1.
(3,4-Dimethoxyphenethyl)carbamoyl Cyanide (3y).11a The compound was prepared from 2y
(147.2 mg, 0.5 mmol) by following the general procedure with the following exception: the reaction
performed using 1.5 equiv of 1d (249.9 mg, 0.75 mmol). The reaction time was 15 min. Purification
by flash column chromatography (PE/EA, 40:1 to 15:1) furnished 3y (107.8 mg, 92% yield) as a
colorless solid: Rf = 0.63 (PE/EA, 1:1); mp 87.2−89.0 °C. A rotamerization of 3y was observed in NMR
spectra (19:1 mixture of rotamers). 1H NMR (400 MHz, CDCl3) (major rotamer) δ 6.84 (d, J = 8.0 Hz,
1H), 6.73 (dd, J = 8.1, 2.1 Hz, 1H), 6.68 (d, J = 2.1 Hz, 1H), 6.19 (brs, 1H), 3.879 (s, 3H), 3.875 (s, 3H),
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3.60 (q, J = 6.8 Hz, 2H), 2.82 (t, J = 6.9 Hz, 2H); C{1H} NMR (100 MHz, CDCl3) (major rotamer) δ
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149.3, 148.2, 143.3, 129.9, 120.8, 111.9, 111.8, 111.6, 56.1, 56.0, 41.7, 34.4.
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(2-(Thiophen-2-yl)ethyl)carbamoyl Cyanide (3z). The compound was prepared from 2z (120.1 mg,
0.5 mmol) by following the general procedure with the following exception: the reaction performed
using 1.5 equiv of 1d (249.9 mg, 0.75 mmol). The reaction time was 15 min. Purification by flash
column chromatography (PE/EA, 40:1 to 10:1) furnished 3z (81.1 mg, 90% yield) as a colorless oil: Rf
= 0.42 (PE/EA, 4:1). A rotamerization of 3z was observed in NMR spectra (19:1 mixture of rotamers).
1H NMR (400 MHz, CDCl3) (major rotamer) δ 7.21 (dd, J = 5.2, 1.2 Hz, 1H), 6.99−6.97 (m, 1H),
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6.88−6.87 (m, 1H), 6.54 (brs, 1H), 3.63 (q, J = 6.4 Hz, 2H), 3.10 (t, J = 6.6 Hz, 2H); C{1H} NMR (100
MHz, CDCl3) (major rotamer) δ 143.3, 139.5, 127.5, 126.1, 124.8, 111.5, 41.8, 29.1; HRMS (EI-TOF)
m/z [M − HCN]+ calcd for C7H7NOS 153.0243, found 153.0246.
(3-Phenylpropyl)carbamoyl Cyanide (3aa). The compound was prepared from 2aa (124.1 mg, 0.5
mmol) by following the general procedure with the following exception: the reaction performed
using 1.5 equiv of 1d (249.9 mg, 0.75 mmol). The reaction time was 30 min. Purification by flash
column chromatography (PE/EA, 40:1 to 10:1) furnished 3aa (82.8 mg, 88% yield) as a colorless oil:
Rf = 0.53 (PE/EA, 4:1). A rotamerization of 3aa was observed in NMR spectra (19:1 mixture of
rotamers). 1H NMR (400 MHz, CDCl3) (major rotamer) δ 7.24−7.21 (m, 2H), 7.17−7.08 (m, 2H), 6.53
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(brs, 1H), 3.27 (q, J = 6.9 Hz, 2H), 2.59 (t, J = 7.6 Hz, 2H), 1.82 (p, J = 7.5 Hz, 2H); C{1H} NMR (100
MHz, CDCl3) (major rotamer) δ 143.3, 140.5, 128.8, 128.4, 126.5, 111.7, 40.3, 33.0, 30.2; HRMS
(EI-TOF) m/z [M − HCN]+ calcd for C10H11NO 161.0835, found 161.0835.
1,4-Phenylenedicarbamoyl Cyanide (3ab). The compound was prepared from 2ab (167.1 mg, 0.5
mmol) by following the general procedure with the following exception: the reaction performed
using 3 equiv of 1d (499.9 mg, 1.5 mmol) in dry MeCN (5.0 mL). The reaction time was 60 min.
Purification by flash column chromatography (PE/EA, 30:1 to 5:1) furnished 3t (101.7 mg, 95% yield)
as a yellow solid: Rf = 0.58 (PE/EA, 1:1); mp >280 °C; 1H NMR (400 MHz, DMSO-d6) δ 11.92 (s, 2H),
7.60 (s, 4H); 13C{1H} NMR (100 MHz, DMSO-d6) δ 140.6, 134.0, 121.0, 112.4; HRMS (EI-TOF) m/z [M
– H2C2N2]+ calcd for C8H4N2O2 160.0267, found 160.0268.
Benzyl(methyl)carbamoyl Cyanide (3ac).11f The compound was prepared from 2ac (117.1 mg, 0.5
mmol) by following the general procedure with the following exception: the reaction performed at
80 °C. The reaction time was 30 min. Purification by flash column chromatography (PE/EA, 40:1 to
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20:1) furnished 3ac (78.4 mg, 90% yield) as a colorless oil: Rf = 0.49 (PE/EA, 5:1). A rotamerization of
3ac was observed in NMR spectra (1:1 mixture of rotamers). 1H NMR (400 MHz, CDCl3) δ 7.36−7.33
(m, 1H), 7.33−7.31 (m, 2H), 7.30−7.27 (m, 3H), 7.20−7.16 (m, 4H), 4.69 (s, 2H), 4.52 (s, 2H), 3.10 (s,
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3H), 2.84 (s, 3H); C{1H} NMR (100 MHz, CDCl3) δ 145.3, 144.9, 134.3, 133.9, 129.4, 129.2, 128.9,
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128.60, 128.57, 127.7, 110.9, 110.6, 54.8, 50.5, 35.5, 32.3.
Diethylcarbamoyl Cyanide (3ad).11b The compound was prepared from 2ad (93.1 mg, 0.5 mmol)
by following the general procedure with the following exception: the reaction performed at 80 °C.
The reaction time was 30 min. Purification by flash column chromatography (PE/EA, 40:1) furnished
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3ad (52.4 mg, 83% yield) as a colorless oil: Rf = 0.53 (PE/EA, 3:1); H NMR (400 MHz, CDCl3) δ 3.62
(q, J = 7.2 Hz, 2H), 3.44 (q, J = 7.2 Hz, 2H), 1.30 (t, J = 7.2 Hz, 3H), 1.18 (t, J = 7.2 Hz, 3H); 13C{1H} NMR
(100 MHz, CDCl3) δ 144.4, 110.9, 43.8, 40.1, 14.6, 12.5.
4-Methylpiperidine-1-carbonyl Cyanide (3ae).11f The compound was prepared from 2ae (106.1 mg,
0.5 mmol) by following the general procedure with the following exception: the reaction performed
at 80 °C. The reaction time was 30 min. Purification by flash column chromatography (PE/EA, 40:1
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to 30:1) furnished 3ae (58.6 mg, 77% yield) as a colorless oil: Rf = 0.48 (PE/EA, 5:1); H NMR (400
MHz, CDCl3) δ 4.35−4.41 (m, 1H), 4.20−4.15 (m, 1H), 3.21 (td, J = 13.1, 3.0 Hz, 1H), 2.75 (td, J = 12.9,
3.1 Hz, 1H), 1.85−1.62 (m, 3H), 1.26−1.07 (m, 2H), 0.97 (d, J = 6.4 Hz, 3H); C{1H} NMR (100 MHz,
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CDCl3) δ 143.2, 110.6, 47.6, 42.5, 34.3, 33.1, 30.8, 21.4.
Methyl 2-((Cyanocarbonyl)amino)thiophene-3-carboxylate (3af). The compound was prepared
from 2af (135.1 mg, 0.5 mmol) by following the general procedure with the following exception: the
reaction performed at 80 °C. The reaction time was 10 min. Purification by flash column
chromatography (PE/EA, 50:1 to 40:1) furnished 3af (91.4 mg, 87% yield) as a colorless solid: Rf =
0.45 (PE/EA, 5:1); mp 111.2−112.8 °C;1H NMR (400 MHz, CDCl3) δ 11.76 (brs, 1H), 7.28 (d, J = 5.7 Hz,
1H), 6.96 (d, J = 5.7 Hz, 1H), 3.94 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 165.8, 145.1, 139.1, 124.5,
119.2, 116.0, 110.9, 52.6; HRMS (EI-TOF) m/z [M]+ calcd for C8H6N2O3S 210.0094, found 210.0092.
1,3-Dicyclohexylimidazolidine-2,4,5-trione (4).16a A colorless solid. Rf = 0.41 (PE/EA, 10:1); mp
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176.0−176.4 °C; H NMR (400 MHz, CDCl3) δ 4.00 (tt, J = 12.4, 3.9 Hz, 2H), 2.11−2.01 (m, 4H),
1.87−1.84 (m, 4H), 1.75−1.66 (m, 6H), 1.38−1.17 (m, 6H); C{1H} NMR (100 MHz, CDCl3) δ 156.6,
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153.6, 52.6, 29.7, 25.8, 24.9; HRMS (ESI-TOF) m/z [M + Na]+ calcd for C15H22N2O3Na 301.1523, found
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Gram-scale Reaction. A flame-dried 100 mL Schlenk flask was charged with 2a (1.03 g, 5 mmol,
1.0 equiv), DCID 1d (1.75 g, 5.25 mmol, 1.05 equiv), and anhydrous MeCN (20 mL) in sequence
under an argon atmosphere. The reaction mixture was stirred at 25 °C for 15 min. Then removing
the organic solvent in a vacuum and purification of the residue via flash column chromatography
(PE/EA, 40:1 to 30:1) afforded the desired product 3a (0.69 g, 94% yield).
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Transformations of Cyanoformamide 3a. An oven-dried 10 mL Schlenk tube was charged with 3a
(73.1 mg, 0.5 mmol), Boc2O (272.8 mg, 1.25 mmol), CoCl2·6H2O (178.4 mg, 0.75 mmol), and MeOH
(4.0 mL) in sequence, followed by adding NaBH4 (75.7 mg, 2 mmol) in one portion at 0 °C. After 3 h
stirring at 0 °C, the reaction mixture was quenched with saturated NH4Cl aqueous solution (ca. 5
mL), then taken up to 1 M NaOH (25 mL) and extracted with ethyl acetate (38 mL × 3). The
combined organic phase was dried over anhydrous Na2SO4 and concentrated under reduced
pressure. The resulting residue was purified by flash column chromatography (PE/EA, 20:1 to 5:1) to
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furnish 5 as a colorless solid (113.9 mg, 91% yield). Rf = 0.50 (PE/EA, 2:1); mp 142.9−144.5 °C; H
NMR (400 MHz, CDCl3) δ 8.37 (brs, 1H), 7.51 (d, J = 7.6 Hz, 2H), 7.31 (t, J = 7.8 Hz, 2H), 7.11 (t, J = 7.4
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Hz, 1H), 5.44 (brs, 1H), 3.94 (s, 2H), 1.47 (s, 9H); C{1H} NMR (100 MHz, CDCl3) δ 168.0, 156.7,
137.6, 129.1, 124.6, 120.1, 80.8, 45.7, 28.4; HRMS (ESI-TOF) m/z [M + H]+ calcd for C13H19N2O3
251.1390, found 251.1394. The spectra data were consistent with values reported in the
literature.25
To a solution of 3a (73.1 mg, 0.5 mmol) and nBu2Sn(O) (10.5 mg, 0.04 mmol) in anhydrous
toluene (9 mL) was added trimethylsilyl azide (195.9 mg, 1.7 mmol) at room temperature. The
resulting mixture was then stirred overnight at 80 °C. After cooling to room temperature, the
mixture was concentrated and purified by flash column chromatography (DCM/MeOH, 10:1) to give
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6 as a colorless solid (82.3 mg, 87% yield). Rf = 0.54 (DCM/MeOH, 5:1); H NMR (400 MHz,
DMSO-d6) δ 10.17 (brs, 1H), 7.84 (d, J = 8.0 Hz, 2H), 7.32 (t, J = 7.8 Hz, 2H), 7.06 (t, J = 7.4 Hz, 1H);
13C{1H} NMR (100 MHz, DMSO-d6) δ 158.7, 157.0, 138.9, 128.6, 123.6, 120.2; HRMS (ESI-TOF) m/z
[M + Na]+ calcd for C8H7N5ONa 212.0543, found 212.0554.
Hydroxylamine hydrochloride (173.7 mg, 2.5 mmol) was added to a solution of 3a (146.2 mg, 1.0
mmol) in dry pyridine (2.0 mL). The resulting mixture was stirred at 50 °C for 1 h. Subsequently, dry
toluene (14 mL) and benzoyl chloride (154.6 mg, 1.1 mmol) was added and the mixture was
refluxed for 1.5 h. After that, TBAF (1.0 M solution in THF, 0.5 mL) was added to the reaction
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mixture and refluxed for days. Upon completion of the reaction (monitored by TLC), the mixture
was diluted with 5% aqueous HCl (40 mL) and extracted with EtOAc (40 mL × 3). The combined
organic phase was washed with water (25 mL × 2), dried over anhydrous Na2SO4, and evaporated in
vacuum. The resulting residue was purified by column chromatography (PE/EA, 25:1 to 10:1) to
afford 7 as a colorless solid (148.6 mg, 56% overall yield). Rf = 0.38 (PE/EA, 5:1); mp 134.4−135.7 °C;
1H NMR (400 MHz, CDCl3) δ 8.79 (s, 1H), 8.23−8.20 (m, 2H), 7.75−7.73 (m, 2H), 7.68−7.64 (m, 1H),
7.59−7.55 (m, 2H), 7.43−7.39 (m, 2H), 7.23−7.19 (m, 1H); 13C{1H} NMR (100 MHz, CDCl3) δ 177.2,
164.3, 154.1, 136.8, 133.8, 129.5, 129.4, 128.6, 125.6, 123.3, 120.3; HRMS (ESI-TOF) m/z [M + H]+
calcd for C15H12N3O2 266.0924, found 266.0930.
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Confirmation of the Formation of Acetyl Chloride. A 10 mL dry Schlenk tube was charged with
the substrate 2c (236.2 mg, 1 mmol, 1.0 equiv), DCID 1d (400.0 mg, 1.2 mmol, 1.2 equiv), and
anhydrous MeCN (5.0 mL) under an argon atmosphere. Then the reaction mixture was stirred at
25 °C for 10 min (complete conversion of 2c). The aniline (274 μL, 279.4 mg, 3 mmol, 3.0 equiv) was
added in one portion. After stirring for an additional 15 minutes, the mixture was diluted with DCM
(25 mL) and washed with saturated brine (20 mL × 2). The organic phase was dried with anhydrous
Na2SO4 and concentrated. The resulting residue was purified by column chromatography (PE/EA,
10:1 to 2:1) to afford N-Phenylacetamide as a colorless solid (93.3 mg, 69% yield). Rf = 0.43 (PE/EA,
1:1); mp 110.5−111.8 °C; 1H NMR (400 MHz, CDCl3) δ 7.76 (brs, 1H), 7.50 (d, J = 7.6 Hz, 2H), 7.30 (t, J
13
= 7.8 Hz, 2H), 7.10 (t, J = 7.4 Hz, 1H), 2.16 (s, 3H); C{1H} NMR (100 MHz, CDCl3) δ 168.8, 138.0,
129.1, 124.4, 120.1, 24.6; HRMS (ESI-TOF) m/z [M + Na]+ calcd for C8H9NONa 158.0576, found
158.0579. The spectra data were consistent with values reported in the literature.26
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the ACS Publications website.
1H and 13C NMR spectra for new starting materials and products (PDF)
AUTHOR INFORMATION
Corresponding Authors
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*E-mail: zjli@njtech.edu.cn.
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*E-mail: guok@njtech.edu.cn.
ORCID
9
Zhenjiang Li: 0000-0002-1100-7297
Kai Guo: 0000-0002-0013-3263
Notes
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The authors declare no competing finacial interest.
ACKNOWLEDGEMENTS
The support of this work by the National Natural Science Foundation of China (U1463201 and
21522604), the National Key Research and Development Program of China (2017YFC1104802), the
Natural Science Foundation of Jiangsu Province, China (BK20150031), the Jiangsu National
Synergetic Innovation Center for Advanced Materials (SICAM), the Priority Academic Program
Development of Jiangsu Higher Education Institutions (PAPD), and the Top-Notch Academic
Programs Project of Jiangsu Higher Education Institutions (TAPP) is gratefully acknowledged.
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