Solvent-Free Synthesis of Cyanoformamides from Carbamoyl Imidazoles

Article abstract of DOI:10.1002/ejoc.201700974

A straightforward and solvent-free synthesis of various secondary and tertiary cyanoformamides from carbamoyl imidazoles and TMSCN has been developed. Both cyclic and acyclic carbamoyl imidazoles react smoothly to form the relevant cyanoformamides in excellent yields, often within minutes.

Full text of DOI:10.1002/ejoc.201700974

A Journal of
Accepted Article
Title: Solvent-free synthesis of cyanoformamides from carbamoyl
imidazoles
Authors: Jeremy Nugent, Sarah G. Campbell, Yen Vo, and Brett D.
Schwartz
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10.1002/ejoc.201700974
European Journal of Organic Chemistry
FULL PAPER
Cyanoformamide synthesis
Jeremy Nugent, Sarah G. Campbell,
Yen Vo, and Brett D. Schwartz
Page No. – Page No.
Secondary and tertiary cyanoformamides have been synthesised with a solvent-
free approach from carbamoyl imidazoles and TMSCN. This method negates the
need to use large excesses of toxic reagents and is ammenable to large-scale syn-
thesis.
Solvent-free synthesis of cyanofor-
mamides from carbamoyl imidazoles
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10.1002/ejoc.201700974
European Journal of Organic Chemistry
Solvent-free synthesis of cyanoformamides from carbamoyl imid-
azoles
Jeremy Nugent, [a] Sarah G. Campbell,[a] Yen Vo,[a] and Brett D. Schwartz*[a,b]
Abstract: A straightforward and solvent-free synthesis of various secondary and tertiary cyanoformamides from carbamoyl imidazoles and
TMSCN has been developed. Both cyclic and acyclic carbamoyl imidazoles react smoothly to form the relevant cyanoformamides in excellent
yields, often within minutes.
acetamides, ammonium acetate and a hypervalent iodine oxi-
dant use starting materials which are not easily sourced, require
Introduction
extended reaction sequences to prepare and often result in diffi-
cult purifications.12 The development of convenient and green
methods for the synthesis of cyanoformamides is an outstanding
challenge in synthetic chemistry. Herein we present a methodol-
ogy that is a significant advancement towards achieving this
goal.
The increasing number of recent synthetic applications of cy-
anoformamides have highlighted the need for more efficient syn-
thetic routes to access these compounds. For example, cy-
anoformamides have been used for intramolecular alkene cy-
anoamidation,1 enantioselective synthesis of disubstituted oxin-
doles,2 the synthesis of N-hydroxy ureas,3 lactams, tetrazoles4
and various other heterocyclic compounds.5 Furthermore, N-
methoxy-N-methylcyanoformamide has recently been used as a
carbonyl dication synthon in the synthesis of unsymmetrical ke-
tones and as a means to install Weinreb amide functionality.6
The discovery of two cyanoformamide natural products, ceratin-
amine and 7-hydroxyceratinamine,7 further illustrates the im-
portance of this motif; the former compound has been shown to
possess antifouling properties.
Results and Discussion
Recently, our group reported a facile synthesis of N-methoxy-
N-methylcyanoformamide through TMSCN-mediated cyanation
of a carbamoyl imidazole precursor.6 To extend our previous
work we now report the synthesis of a range of secondary and
tertiary cyanoformamides via a similar method.
Initial investigations utilised tertiary tetrahydroisoquinoline car-
bamoyl imidazole 1a as a model substrate to optimise reaction
conditions (Table 1). First, a range of solvents were screened.
Neither THF nor toluene gave appreciable amounts of product
(entries 1-2), however, when conducting the reaction neat with
2.00 eq. of TMSCN, the cyanoformamide 2a was formed in good
yield (entry 3). Further experimentation showed that a very high-
yielding reaction proceeded when using only 1.05 eq. of TMSCN,
with optimal conditions of 140 °C under microwave irradiation
(entries 4-5).
Figure 1. Cyanoformamide-containing natural products.
Table 1. Optimisation studies.
Currently, most routes to cyanoformamides suffer from numer-
ous drawbacks. For example, traditional syntheses of cyanofor-
mamides from an amine and carbonyl cyanide, or from car-
bamoyl chlorides and a cyanide ion, require the use of toxic and
potentially explosive reagents.8 More recent advances include
the reaction of primary amines with carbon dioxide followed by a
cyanophosphonate;9 the reaction of 1-acyl-1-carbamoyl oximes
with POCl3,10 and; the cyanocarbonylation of amines with iso-
nitroso-Meldrum's acid.11 All of these reactions require the use
of exotic and commercially unavailable reagents. Similarly, the
recently reported synthesis of cyanoformamides from 2-oxo-
[a] Isolated yield.
[a]
[b]
Research School of Chemistry, Institute of Advanced Studies, The
Australian National University, Canberra, ACT 2601, Australia
(current address)
E-mail: brett.schwartz@anu.edu.au
Griffith Institute for Drug Discovery, Griffith University, Don Young
Road, Nathan, QLD 4111, Australia
With optimal conditions determined, we then evaluated reac-
tion scope. Various tertiary carbamoyl imidazole compounds
were reacted and the results are summarized in Table 2. Pyrrol-
lidines (2b-2d), piperidines (2e-2g), morpholine (2h), pipera-
Supporting information for this article is given via a link at the end of
the document.((Please delete this text if not appropriate))
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10.1002/ejoc.201700974
European Journal of Organic Chemistry
zines (2i-2j), tetrahydropyrrolopyrazine (2k), aniline (2l), dime-
thylamine (2m) and propargyl amine (2n) derived carbamoyl im-
idazoles readily underwent cyanation with TMSCN to form the
product cyanoformamides, isolated in excellent yields (70-
95%).13 The azetidine (2o) and cubane carbamoyl imidazoles
(2p) decomposed under standard conditions; however, excellent
yields were achieved when conducting the reactions at lower
temperatures. Furthermore, the large-scale synthesis of the syn-
thetically-useful5b,14 morpholine cyanoformamide was explored
under conventional heating in a sealed tube. In this manner, 2h
was isolated in an excellent yield on exposure to 1.05 eq. of
TMSCN at 100 °C.
Table 2. Synthesis of tertiary cyanoformamides.
O
O
TMSCN (1.05 eq.), neat
R1
R1
N
N
NC
N
R2
R2
N
1
2
O
O
O
NC
N
NC
N
NC
N
F
F
2b 81% [a]
2c 83%[a]
2d 84%[a]
The formation of secondary cyanoformamides was more chal-
lenging. Using N-benzyl carbamoyl imidazole (1q) as a model
substrate, we optimized conditions for secondary cyanoforma-
mide synthesis (Table 3). When using conventional heating at
similar temperatures and stoichiometry to that of the tertiary sys-
tem, the major product isolated was 5-iminoimidazolidine-2,4-di-
one 3; only low yields of cyanoformamide (2q), along with a con-
siderable amount of staring material, were isolated (entry 1). Per-
forming the reaction at a lower temperature increased the yield
of cyanoformamide 2q, however, considerable amounts of start-
ing material and dimer were still present (entry 2). Full conver-
sion of starting material was observed when the stoichiometry
was changed to 2.00 eq. of TMSCN, but considerable amounts
of the 5-iminoimidazolidine-2,4-dione by-product were present
(entries 3-4). The unwanted dimerization reaction has been
shown, in the case of alkyl-substituted cyanoformamides, to only
occur at elevated temperatures,15 thus, we expected lower tem-
peratures would facilitate an increase in yield of the cyanoforma-
mide products. When the reaction was conducted at 70 °C a sig-
nificant reduction in iminodione product was observed and ex-
cellent yields of N-benzylcyanoformamide (2q) were achieved
after only 3 minutes at this temperature (entry 5).
O
O
O
NC
N
NC
N
NC
N
N
F
F
2g 82%[a]
2e 87%[a]
2f 95%[a]
O
O
NC
N
NC
N
N
O
N
CF3
O
2i 92%[a]
2h 86%[a], 88%[b]
O
O
NC
N
NC
N
NC
N
N
N
2j 72%[a]
2k 82%[a]
2l 84%[a]
O
O
N
O
NC
N
NC
NC
N
We could now apply these optimized conditions for the syn-
thesis of various secondary cyanoformamides (Table 4). In all
cases, the reaction was near complete within minutes at 70 °C.
Electron rich 4-methoxybenzyl and 2,4-dimethoxybenzyl car-
bamoyl imidazoles both underwent a clean and high-yielding re-
action to afford cyanoformamides with no trace of cyclisation
products (2r-s).16 Phenethylamine, cyclic and acyclic aliphatic
carbamoyl imidazoles all readily afforded the expected products
in excellent yields (2t-w). In all examples, only trace dimeric
products were observed.
2m 92%[a]
2n 70%[a]
2o 95%[c]
O
N
NC
2p 70%[c]
[a] 1 h, 140 °C, 200 W, µw. [b] 10 mmol scale: 18 h, 100 °C, sealed tube. [c]
2 h, 100 °C, 200 W, µw.
Table 3. Optimisation studies.
O
O
O
conditions
N
N
NC
N
N
N
H
H
N
HN
O
1q
2q
3
Entry
Conditions[a]
2q[b]
3[b]
1q[b]
1
2
3
4
TMSCN (1.05 eq.), neat, 100 °C, 10 min
TMSCN (1.05 eq.), neat, 70 °C, 60 min
TMSCN (2 eq.), neat, 100 °C, 10 min
TMSCN (2 eq.), neat, 85 °C, 5 min
TMSCN (2 eq.), neat, 70 °C, 3 min
24%
30%
26%
70%
83%
44%
36%
62%
15%
trace
15%
25%
trace
trace
trace
5
[a] Sealed tube. [b] Isolated yield.
3
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10.1002/ejoc.201700974
European Journal of Organic Chemistry
Table 4. Synthesis of secondary cyanoformamides.
In summary, we have reported a facile and operationally sim-
ple method for the synthesis of secondary and tertiary cyanofor-
mamides. This methodology is attractive as the starting materials
and reagents are easily sourced, no prolonged reaction se-
quences are needed and only a small excess of cyanide source
is required.
TMSCN (2 eq.),
neat , 70 °C,
3-10 min
O
O
R1
R1
N
N
H
NC
N
H
N
1
2
O
O
OMe
NC
N
NC
N
H
H
Experimental Section
OMe
OMe
2r 94%[a]
2s 89%[a]
General Experimental Procedures
Unless otherwise specified, proton (1H) and carbon (13C) NMR spectra
were recorded at 18 °C in base-filtered CDCl3 on a Varian spectrometer
operating at 400 or 500 MHz for proton and 100 or 125 MHz for carbon
nuclei. For 1H NMR spectra, signals arising from the residual protio-forms
of the solvent were used as the internal standards. 1H NMR data are rec-
orded as follows: chemical shift (δ) [multiplicity, coupling constant(s) J
(Hz), relative integral] where multiplicity is defined as: s = singlet; d =
doublet; t = triplet; q = quartet; m = multiplet; mc = centred multiplet; br =
broad or combinations of the above. The signal due to residual CHCl3
appearing at δH 7.26 and the central resonance of the CDCl3 “triplet” ap-
pearing at δC 77.16 were used to reference 1H and 13C NMR spectra,
respectively. Where possible, major and minor rotamers have been indi-
cated. Infrared spectra (νmax) were recorded on a Perkin-Elmer 1800 Se-
ries FTIR Spectrometer (thin films on KBr plates) or Perkin–Elmer UATR
Spectrum Two spectrometer (thin film or solid). A VG Fisons AutoSpec
mass spectrometer was used to obtain low- and high-resolution electron
impact (EI) mass spectra. Low- and high-resolution electrospray (ESI)
mass spectra were obtained on a VG Quattro II triple-quadrupole MS in-
strument operating in positive ionization mode. Melting points were meas-
ured on an Optimelt automated melting point system and are uncor-
rected. Analytical thin layer chromatography (TLC) was performed on alu-
minum-backed 0.2 mm thick silica gel 60 F254 plates as supplied by
Merck. Eluted plates were visualized using a 254 nm UV lamp and/or by
treatment with a suitable dip followed by heating. These dips included
phosphomolybdic acid : ceric sulfate : sulfuric acid (conc.) : water (37.5 g
: 7.5 g : 37.5 g : 720 mL) or potassium permanganate : potassium car-
bonate : 5% sodium hydroxide aqueous solution : water (3 g : 20 g: 5 mL
: 300 mL). Flash chromatographic separations were carried out following
protocols defined by Still et al.18 with silica gel 60 (40-63 mm) as the sta-
tionary phase and using the AR- or HPLC-grade solvents indicated. Start-
ing materials and reagents were generally available from the Sigma-Al-
drich, Merck, AK Scientific Inc., Matrix Scientific Chemical Companies
and were used as supplied. Drying agents and other inorganic salts were
purchased from the AJAX, BDH or Unilab Chemical Companies. Tetra-
hydrofuran (THF), methanol and dichloromethane (DCM) were dried us-
ing a Glass Contour solvent purification system that is based upon a tech-
nology originally described by Grubbs et al.19 Triethylamine and DMSO
were freshly distilled over calcium hydride before use. Where necessary,
reactions were performed under a nitrogen atmosphere. Microwave facil-
itated reactions were carried out using a CEM Explorer system with con-
ditions specified. Reactions with trimethylsilyl cyanide were conducted in
a fully operational fumehood with appropriate personal protective equip-
ment.
OMe
OMe
O
O
NC
N
NC
NC
N
H
H
2t 87%a
2u 79%[a]
O
O
N
H
NC
N
H
2w 83%[a]
2v 74%[a]
[a] Isolated yield.
On the basis of our observations and literature reports, a plau-
sible mechanism for the formation of the cyanoformamide prod-
ucts is shown in Scheme 1. Secondary carbamoyl imidazole
compounds equilibrate with their isocyanate species (pathway
a);17 cyanation of this intermediate readily affords the product cy-
anoformamide. While fully substituted carbamoyl imidazoles are
unlikely to equilibrate with their isocyanate species, a second
possible mechanism exists that accommodates formation of both
secondary and tertiary cyanoformamides. Activation of the car-
bonyl, via silylation of either the carbonyl or the imidazole nitro-
gen, followed by cyanation concomitant with the loss of TMS-
imidazole, affords the tertiary cyanoformamide (pathway b). 5-
Iminoimidazolidine-2,4-dione products form via reaction be-
tween an isocyanate and a secondary cyanoformamide, the
mechanism of which has been proposed previously.Error! Bookmark
not defined.
Scheme 1. Reaction mechanism.
pathway b
R
= alkyl or H
CN
R
O
TMS
O
TMSCN
O
CN
R
N
N
N
R
N
N
N
N
N
N
N
TMS
H
N
pathway a
R = H
N
+

N
Specific Chemical Transformations
TMS
General Procedure A – Padiya’s ‘In water’ synthesis of carbamoyl
imidazoles.
+
HCN
O

O
•
R
N
NC
N
Following a modified procedure.20 A 250 mL conical flask in an ice-
water bath was charged with crushed ice (10 g), a saturated aqueous
solution of sodium hydrogen carbonate (10 mL), water (10 mL), free
amine or hydrochloride (1 mmol) and vigorously stirred whilst treated,
portion-wise, with the specified amount of N,N’-carbonyldiimidazole (CDI)
(1-2 mmol) over a period of two minutes to avoid frothing. After 0.25 h the
reaction was worked up by the indicated method. These methods were
Conclusions
4
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10.1002/ejoc.201700974
(1b):
European Journal of Organic Chemistry
either: i) collection of solids by vacuum filtration followed by washing with
water (20 mL) and drying under high vacuum (1 mmHg); or, ii) the mixture
was extracted with DCM (3 × 15 mL) followed by washing of the combined
organic extracts with water (15 mL) then brine (10 mL). The combined
layers were dried (Na2SO4), concentrated in vacuo and when necessary,
the crude product purified by flash chromatography, eluting with the sol-
vent system specified.
(1H-Imidazol-1-yl)(octahydro-2H-isoindol-2-yl)methanone
Prepared according to General Procedure A(ii) from cis-hexahydroisoin-
doline (2.02 g, 16.1 mmol) and CDI (3.39 g, 20.9 mmol) to afford 1b (2.70
g, 76%) as a pale-orange viscous oil which required no further purifica-
tion: 1H NMR (CDCl3, 400 MHz) δ 8.02 (app. t, J = 0.9 Hz, 1H), 7.35 (app.
t, J = 1.4 Hz, 1H), 7.07 (dd, J = 1.4, 0.9 Hz, 1H), 3.62 (dd, J = 10.8, 7.1
Hz, 2H), 3.55 – 3.44 (m, 2H), 2.36 – 2.26 (m, 2H), 1.72 – 1.33 (m, 8H);
13C NMR (CDCl3, 100 MHz) mixture of rotamers δ 150.3, 136.9, 129.6,
117.8, 77.2, 53.7, 51.7, 38.1, 35.9, 25.5, 22.5; MS (+)-LRESI m/z (%) 220
(35) [M + H]+, 242 (100) [M + Na]+, 152 (33); MS (+)-HRESI calcd. for
C12H18N3O [M + H]+ 220.1444 found 220.1451; νmax 2926, 2855, 1682,
1406, 1210, 750 cm-1.
General Procedure B – Batey’s synthesis of carbamoyl imidazoles.
Following a modified procedure.21 A mixture of amine hydrochloride
(3.0 mmol), DMF (1 mL) and acetonitrile (4 mL) under and atmosphere of
nitrogen was treated with CDI (535 mg, 3.3 mmol) and stirred for 18 h.
The mixture was concentrated in vacuo to afford a residue which after
flash chromatography in the solvent specified afforded the carbamoyl im-
idazole.
Octahydro-2H-isoindole-2-carbonyl cyanide (2b): Prepared ac-
cording to General Procedure C [140 °C, 1 h, ramp time 5 minutes, 200
W, PowerMax (cooling with N2(g))] from 1b (219 mg, 1.00 mmol) and
TMSCN (131 µL, 1.05 mmol) to afford after flash chromatography (1:2,
EtOAc:40-60 petroleum ether) 2b (144 mg, 81%) as a yellow oil: 1H NMR
(CDCl3, 400 MHz) mixture of rotamers δ 3.74 (dd, J = 10.6, 7.0 Hz, 1H),
3.62 (dd, J = 10.6, 5.7 Hz, 1H), 3.49 (dd, J = 12.8, 7.0 Hz, 1H), 3.39 (dd,
J = 12.8, 5.7 Hz, 1H), 2.39 – 2.29 (m, 2H), 1.72 – 1.60 (m, 2H), 1.57 –
1.37 (m, 6H). 13C NMR (CDCl3, 100 MHz) δ 143.5, 111.3, 52.0, 49.9,
36.9, 36.3, 25.6, 25.5, 22.6, 22.4. (+)-LRESI m/z (%) 179 (100) [M + H]+.
MS (+)-HRESI calcd. for C10H15N2O [M + H]+ 179.1179; found, 179.1181;
νmax 2929, 2859, 2231, 1669, 1406 cm-1.
General Procedure C – Microwave-assisted synthesis of cyanofor-
mamides.
A 10 mL snap-cap microwave vessel fitted with a septum and magnetic
stirring bar under an atmosphere of nitrogen was charged with carbamoyl
imidazole (1.00 eq.) and trimethylsilyl cyanide (TMSCN, CAUTION!)
(1.05 eq.). The septum was removed and replaced with a snap-cap then
subjected to the microwave irradiation conditions specified (microwave
reactor in fumehood). The mixture was quenched with an ice-cold aque-
ous solution of NaHCO3 (5 mL) and extracted with DCM (2 × 10 mL) and
the combined organic extracts washed with brine (5 mL). The organic
layer was dried (Na2SO4) and concentrated in vacuo to afford a residue
which was purified by flash chromatography in the solvent system speci-
fied to afford the indicated cyanoformamide.
(Hexahydrocyclopenta[c]pyrrol-2(1H)-yl)(1H-imidazol-1-yl)meth-
anone (1c): Prepared according to General Procedure A(ii) from 3-azabi-
cyclo[3.3.0]octane hydrochloride (2.08 g, 14.10 mmol) and CDI (2.86 g,
17.63 mmol) to afford 1c (2.24 g, 77%) as a pale-yellow oil which required
no further purification: 1H NMR (CDCl3, 400 MHz) δ 7.96 (s, 1H), 7.31 (s,
1H), 7.05 (s, 1H), 3.81 (dd, J = 11.6, 7.0 Hz, 2H), 3.41 (dd, J = 11.4, 2.9
Hz, 2H), 2.78 – 2.66 (m, 2H), 1.92 – 1.80 (m, 2H), 1.80 – 1.73 (m, 1H),
1.70 – 1.59 (m, 1H), 1.53 – 1.43 (m, 2H); 13C NMR (CDCl3, 100 MHz) δ
149.6, 136.9, 129.5, 117.9, 54.4, 43.0, 31.8, 25.5; MS (+)-LRESI m/z (%)
228 (100) [M + Na]+, 138 (20); MS (+)-HRESI calcd. for C11H15N3NaO [M
+ Na]+ 228.1107, found 228.1113; νmax 3121, 2946, 1663, 1420, 1243,
772 cm-1.
General Procedure D - Synthesis of cyanoformamides under conven-
tional heating.
An oven-dried Ace Glass® pressure tube (100 × 25.4 mm, 15 mL) un-
der an atmosphere of nitrogen fitted with a septum and stirrer bar, was
charged with the specified amounts of carbamoyl imidazole and trime-
thylsilyl cyanide. The septum was removed and replaced with a screw-
thread plug (front sealed with an FETFE O-ring) and heated with stirring
in a silicon bath at the specified temperature behind a safety shield. After
the specified time, the silicon oil bath was removed and the tube was then
cooled in ice water and quenched with an ice-cold aqueous solution of
NaHCO3 (5 mL). The mixture was extracted with DCM (2 × 10 mL) and
the combined organic extracts washed with brine (5 mL). The organic
layer was dried (Na2SO4) and concentrated in vacuo to afford a residue
which was purified by flash chromatography in the solvent system speci-
fied to afford the indicated cyanoformamide.
Hexahydrocyclopenta[c]pyrrole-2(1H)-carbonyl cyanide (2c): Pre-
pared according to General Procedure C [140 °C, 1 h, ramp time 5
minutes, 200 W, PowerMax (cooling with N2(g))] from 1c (205 mg, 1.00
mmol) and TMSCN (131 µL, 1.05 mmol) to afford after flash chromatog-
raphy (1:2, EtOAc:40-60 petroleum ether) 2c (136 mg, 83%) as a yellow
oil: 1H NMR (CDCl3, 400 MHz) δ 3.93 (dd, J = 11.5, 7.9 Hz, 1H), 3.69 (dd,
J = 13.4, 7.9 Hz, 1H), 3.54 (dd, J = 11.5, 4.3 Hz, 1H), 3.32 (dd, J = 13.4,
4.3 Hz, 1H), 2.83 – 2.72 (m, 2H), 1.96 – 1.85 (m, 2H), 1.82 – 1.69 (m,
1H), 1.71 – 1.61 (m, 1H), 1.54 – 1.42 (m, 2H).13C NMR (CDCl3, 100 MHz)
δ 142.4, 111.2, 54.1, 51.7, 42.7, 42.4, 32.2, 31.8, 25.6. MS (+)-LRESI m/z
(%) 165 (100) [M + H]+; MS (+)-HRESI calcd. for calcd. for C9H13N2O [M
+ H]+: 165.1022; found, 165.1029; νmax 2952, 2873, 2231, 1667, 1411 cm-
(3,4-Dihydroisoquinolin-2(1H)-yl)(1H-imidazol-1-yl)methanone
(1a): Prepared according to General Procedure A(i) from 1,2,3,4-tetrahy-
droisoquinoline (2.66 g, 20 mmol) and CDI (4.54 g, 28 mmol) to afford,
after filtration, 1a (3.11 g, 68%) as a beige powder: mp 91 – 94 °C; 1H
NMR (CDCl3, 500 MHz) δ 8.12 – 7.77 (m, 1H), 7.27 (app. t, J = 1.4 Hz,
1H), 7.26 – 7.16 (m, 3H), 7.14 – 7.12 (m, 1H), 7.11 – 7.09 (m, 1H), 4.75
(s, 2H), 3.82 (t, J = 6.0 Hz, 2H), 3.01 (t, J = 6.0 Hz, 2H). Spectral data
were consistent with those reported.22
1
.
(3,3-Difluoropyrrolidin-1-yl)(1H-imidazol-1-yl)methanone
(1d):
Prepared according to General Procedure B from 3,3-difluoropyrrolidine
hydrochloride (431 mg, 3.0 mmol), CDI (535 mg, 3.3 mmol), DMF (1 mL)
and acetonitrile (4 mL) to afford after flash chromatography (1:10,
MeOH:DCM), 1d (634 mg 90%) as white crystals: mp 76 – 80 °C; 1H
NMR (CDCl3, 500 MHz) δ 7.99 (s, 1H), 7.30 (s, 1H), 7.12 (s, 1H), 3.97 (t,
J = 12.3 Hz, 2H), 3.90 (t, J = 7.4 Hz, 2H), 2.51 – 2.42 (m, 1H); 13C NMR
(CDCl3, 125 MHz) δ 13C NMR (CDCl3, 125 MHz) δ 162.2, 149.4, 136.5,
129.6, 126.0 (t, JC-F = 248.6 Hz), 117.2, 54.1 (t, JC-F = 32.7 Hz), 46.0, 33.3
(t, JC-F = 23.8 Hz); MS (+)-LRESI m/z (%) 202 (72) [M + H]+, 134 (100);
MS (+)-HRESI calcd. for C8H10F2N3O [M + H]+ 202.0786, found
202.0788; νmax 3149, 1675, 1262, 1122 cm-1.
3,4-Dihydroisoquinoline-2(1H)-carbonyl cyanide (2a): Prepared
according to General Procedure C [140 °C, 1 h, ramp time 5 minutes, 200
W, PowerMax (cooling with N2(g))] from 1a (227 mg, 1.00 mmol) and
TMSCN (131 µL, 1.05 mmol) to afford after flash chromatography (1:2,
EtOAc:40-60 petroleum ether) 2a (170 mg, 91%) as a colorless viscous
oil: 1H NMR (CDCl3, 500 MHz) 0.7:1 mixture of rotamers δ 7.30 – 7.15
(m, 4H), 4.92 (s, 2Hmin), 4.77 (s, 2Hmaj), 4.04 (t, J = 6.0 Hz, 2Hmaj), 3.88
(t, J = 6.2 Hz, 2Hmin), 3.04 (t, J = 6.0 Hz, 2Hmaj), 2.96 (t, J = 6.2 Hz, 2Hmin).
13C NMR (CDCl3, 125 MHz) mixture of rotamers δ 144.0, 143.7, 133.8,
133.0, 130.7, 130.5, 129.0, 128.9, 127.9, 127.5, 127.3, 127.2, 126.6,
126.3, 110.6, 110.5, 48.4, 44.9, 44.6, 40.8, 29.3, 27.9; MS (+)-LREI m/z
(%) 186 (100, M+•), 171 (12), 130 (25), 117 (45), 116 (45), 104 (75), 77
(32); MS (+)-HRESI calcd. for C11H10N2NaO [M + Na]+ 209.0685, found
209.0685; νmax 2231, 1667, 1446, 721 cm-1.
3,3-Difluoropyrrolidine-1-carbonyl cyanide (2d): Prepared accord-
ing to General Procedure C [140 °C, 1 h, ramp time 5 minutes, 200 W,
PowerMax (cooling with N2(g))] from 1d (201 mg, 1.00 mmol) and TMSCN
(131 µL, 1.05 mmol) to afford, after flash chromatography (1:2, EtOAc:40-
5
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201700974
European Journal of Organic Chemistry
60 petroleum ether), 2d (134 mg, 84%) as a yellow oil: 1H NMR (CDCl3,
500 MHz) 0.7:1 mixture of rotamers δ 4.09 (t, J = 11.8 Hz, 1Hmin), 4.02 (t,
J = 7.4 Hz, 1Hmaj), 3.85 (t, J = 12.3 Hz, 1Hmaj), 3.78 (t, J = 7.6 Hz, 1Hmin),
2.58 – 2.44 (m, 2H); 13C NMR (CDCl3, 125 MHz) δ 142.9, 142.8, 125.9 (t,
263 (100) [M + H]+, 195 (48); MS (+)-HRESI calcd. for C14H23N4O [M +
H]+: 263.1866; found, 263.1872; νmax 2930, 1688, 1426, 1275, 749 cm-1.
4-Piperidinopiperidine-1-carbonyl cyanide (2g): Prepared accord-
ing to General Procedure C [140 °C, 1 h, ramp time 5 minutes, 200 W,
PowerMax (cooling with N2(g))] from 1g (262 mg, 1.00 mmol) and TMSCN
(131 µL, 1.05 mmol) to afford, after flash chromatography (1:9,
MeOH:DCM), 2g (180 mg, 82%) as a yellow viscous oil: 1H NMR (CDCl3,
400 MHz) δ 4.50 – 4.38 (m, 1H), 4.27 (m, 1H), 3.25 (ddd, J = 13.3, 12.0,
3.0 Hz, 1H), 2.88 – 2.75 (m, 1H), 2.62 – 2.44 (m, 5H), 2.06 – 1.82 (m,
2H), 1.67 – 1.37 (m, 8H). 13C NMR (CDCl3, 100 MHz) δ 143.1, 110.5,
61.7, 50.3, 46.8, 41.8, 28.6, 27.3, 26.4, 24.7. MS (+)-LRESI m/z (%) 222
(100) [M + H]+. MS (+)-HRESI calcd. for C12H20N3NaO [M + H]+:
222.1606; found, 222.1604; νmax 2932, 2853, 2798, 2228, 1669, 1450,
1432 cm-1.
JC-F = 249.0 Hz), 125.7 (t, JC-F = 250.3 Hz), 110.4, 110.2, 53.9 (t, JC-F
=
33.5 Hz), 52.5 (t, JC-F = 33.6 Hz), 45.4 (t, JC-F = 3.1 Hz), 43.6 (t, JC-F = 3.1
Hz), 33.8 (t, JC-F = 24.7 Hz), 33.0 (t, JC-F = 24.2 Hz); GC/MS EI m/z (%)
160 (94, M+•), 141 (3), 131 (9), 111 (4), 96 (26), 77 (27), 68 (37), 54 (33),
42 (100); MS (+)-HRESI calcd. for C6H6F2N2NaO [M + Na]+ 183.0341,
found 183.0340; νmax 3396, 2916, 2849, 2237, 1688, 1686, 1450, 1423,
1369, 1131, 1116, 925 cm-1;
(1H-Imidazol-1-yl)(piperidin-1-yl)methanone (1e): Prepared ac-
cording to General Procedure A(ii) from piperidine (2.78 mL, 28.0 mmol)
and CDI (5.90 g, 36.6 mmol) to afford, after flash chromatography (1:10,
MeOH:DCM), 1e (3.62 g, 72%): 1H NMR (CDCl3, 400 MHz) δ 7.87 – 7.81
(m, 1H), 7.20 – 7.18 (m, 1H), 7.09 – 7.07 (m, 1H), 3.57 – 3.49 (m, 4H),
1.77 – 1.60 (m, 6H). Spectral data were consistent with those reported.22
4-(1H-Imidazol-1-ylcarbonyl)morpholine (1h): Prepared according
to General Procedure B from morpholine hydrochloride (6.35 g, 49.0
mmol), CDI (7.95 g, 54.0 mmol), DMF (15 mL) and acetonitrile (50 mL) to
afford, after flash chromatography (1:10, MeOH:DCM), 1h (5.15 g, 58 %)
as white crystals: mp 93 – 94 °C; 1H NMR (CDCl3, 400 MHz) δ 7.87 (t, J
= 1.1 Hz, 1H), 7.19 (app. t, J = 1.1 Hz, 1H), 7.10 (t, J = 1.1 Hz, 1H), 3.78
– 3.74 (m, 4H), 3.65 – 3.61 (m, 4H). Spectral data were consistent with
those reported.22
Piperidine-1-carbonyl cyanide (2e): Prepared according to General
Procedure C [140 °C, 1 h, ramp time 5 minutes, 200 W, PowerMax (cool-
ing with N2(g))] from 1e (179 mg, 1.00 mmol) and TMSCN (131 µL, 1.05
mmol) to afford, after flash chromatography (1:2, EtOAc:40-60 petroleum
ether), 2e (120 mg, 87%) as a yellow oil: 1H NMR (CDCl3, 400 MHz) δ
3.76 – 3.67 (m, 2H), 3.62 – 3.53 (m, 2H), 1.78 – 1.66 (m, 4H), 1.64 – 1.58
(m, 2H). Spectral data were consistent with those reported.10
Morpholine-4-carbonyl cyanide (2h): Microwave method: Pre-
pared according to General Procedure C [140 °C, 1 h, ramp time 5
minutes, 200 W, PowerMax (cooling with N2(g))] from 1h (181 mg, 1.00
mmol) and TMSCN (131 µL, 1.05 mmol) to afford, after flash chromatog-
raphy (1:1, EtOAc:40-60 petroleum ether), 2h (120 mg, 86%) as a col-
ourless solid. Conventional heating method: Prepared according to
General Procedure D (100 °C, 18 h) from 1h (1.81 g, 10.00 mmol) and
TMSCN (1.31 mL, 10.5 mmol) to afford, after flash chromatography (1:1,
EtOAc:40-60 petroleum ether), 2h (1.23 g, 88%) as a colourless solid:
mp 59 – 61 °C; 1H NMR (CDCl3, 400 MHz) δ 3.79 – 3.78 (m, 2H), 3.74 –
3.70 (m, 1H), 3.69 – 3.65 (m, 1H). Spectral data were consistent with
those reported.5b
(3,3-Difluoropiperidin-1-yl)(1H-imidazol-1-yl)methanone (1f): Pre-
pared according to General Procedure B from 3,3-difluoropiperidine hy-
drochloride (473 mg, 3.0 mmol), CDI (535 mg, 3.3 mmol), DMF (1 mL)
and acetonitrile (4 mL) to afford, after flash chromatography (1:10,
MeOH:DCM), 1f (664 mg, 88 %) as white crystals: mp 98 – 101 °C; 1H
NMR (CDCl3, 500 MHz) δ 7.89 (s, 1H), 7.22 (s, 1H), 7.12 (s, 1H), 3.74 (t,
J = 11.0 Hz, 1H), 3.60 (dd, J = 5.6, 5.6 Hz, 2H), 2.13 (tt, J = 13.3, 6.4 Hz,
2H), 1.97 – 1.88 (m, 2H); 13C NMR (CDCl3, 125 MHz) δ 151.4, 137.1,
130.3, 118.6 (t, JC-F = 244.7 Hz), 118.0, 52.0 (t, JC-F = 32.8 Hz), 45.7, 32.5
(t, JC-F = 23.5 Hz), 21.8 (t, JC-F = 4.6 Hz); MS (+)-LRESI m/z (%) 216 (95)
[M + H]+, 134 (100); MS (+)-HRESI calcd. for C9H12F2N3O [M + H]+
216.0943, found 216.0940; νmax 3176, 1679, 1434, 1102 cm-1.
(1H-Imidazol-1-yl)(4-(5-(trifluoromethyl)pyridin-2-yl)piperazin-1-
yl)methanone (1i): Prepared according to General Procedure A(i) from
1-(5-(trifluoromethyl)pyridin-2-yl)piperazine (1.00 g, 4.32 mmol) and CDI
(1.40 g, 8.65 mmol) to afford, after filtration, 1i (0.98 g, 70 %) as a white
powder: mp 141 – 145 °C; 1H NMR (CDCl3, 400 MHz) δ 8.43 (s, 1H), 7.92
(s, 1H), 7.70 (dd, J = 9.0, 2.5 Hz, 1H), 7.24 (s, 1H), 7.13 (s, 1H), 6.68 (d,
J = 9.0 Hz, 1H), 3.80 – 3.73 (m, 8H). 13C NMR (CDCl3, 100 MHz) δ 160.0,
151.2, 145.9 (q, JC-F = 4.3 Hz), 137.0, 135.1 (q, JC-F = 3.2 Hz), 130.2,
124.5 (q, JC-F = 270.6 Hz), 118.0, 116.64 (q, JC-F = 33.1 Hz), 106.0, 46.1
(2C), 44.6 (2C). MS (+)-LRESI m/z (%) 348 (100) [M + Na]+; MS (+)-
HRESI calcd. for C14H15F3N5O [M + H]+ 326.1223, found 326.1229; νmax
1679, 1611, 1323, 1239, 1099, 988 cm-1.
3,3-Difluoropiperidine-1-carbonyl cyanide (2f): Prepared according
to General Procedure C [140 °C, 1 h, ramp time 5 minutes, 200 W,
PowerMax (cooling with N2(g))] from 1f (215 mg, 1.00 mmol) and TMSCN
(131 µL, 1.05 mmol) to afford, after flash chromatography (1:2, EtOAc:40-
1
60 petroleum ether), 2f (165 mg, 95%) as a yellow oil: H NMR (CDCl3,
500 MHz) 1:1 mixture of rotamers δ 3.92 (t, J = 10.7 Hz, 1H), 3.84 (t, J =
11.2 Hz, 1H), 3.80 – 3.76 (m, 1H), 3.67 – 3.63 (m, 1H), 2.19 – 2.09 (m,
2H), 1.98 – 1.91 (m, 1H), 1.87 – 1.80 (m, 1H). 13C NMR (CDCl3, 125 MHz)
mixture of rotamers δ 143.9(0), 143.9(86), 118.2 (t, JC-F = 244.9 Hz),
118.0 (t, JC-F = 245.7 Hz), 110.0, 109.8, 52.4 (t, JC-F = 33.3 Hz), 47.3 (t,
JC-F = 34.0 Hz), 46.4, 41.8, 32.5 (t, JC-F = 23.6 Hz), 32.3 (t, JC-F = 23.7
Hz), 22.5 (t, JC-F = 4.7 Hz), 21.2 (t, JC-F = 4.6 Hz); GC/MS EI m/z (%) 174
(100, M+•), 159 (9), 155 (7), 145 (18), 120 (52), 106 (10), 97 (34), 91 (18),
77 (19), 64 (41), 54 (40), 42 (52). MS (+)-HRESI calcd. for C7H8F2N2NaO
[M + Na]+ 197.0497, found 197.0495; νmax 2949, 2234, 1683, 1435, 1375,
1111 cm-1.
4-(5-(Trifluoromethyl)pyridin-2-yl)piperazine-1-carbonyl cyanide
(2i): Prepared according to General Procedure C [140 °C, 1 h, ramp time
5 minutes, 200 W, PowerMax (cooling with N2(g))] from 1i (325 mg, 1.00
mmol) and TMSCN (131 µL, 1.05 mmol) to afford, after flash chromatog-
raphy (1:9, MeOH:DCM), 2i (260 mg, 92%) as white crystals: mp 175 –
178 °C; 1H NMR (CDCl3, 400 MHz) δ 8.43 (s, 1H), 7.71 (dd, J = 9.0, 2.5
Hz, 1H), 6.70 (d, J = 8.9 Hz, 1H), 3.91 – 3.81 (m, 4H), 3.79 – 3.70 (m,
4H). 13C NMR (CDCl3, 100 MHz) δ 159.7, 146.0 (q, JC-F = 4.3 Hz) 143.5,
135.2 (q, JC-F = 3.3 Hz), 124.4 (d, JC-F = 270.5 Hz), 116.9 (q, J = 33.2 Hz),
110.2, 106.1, 46.5, 45.0, 44.2, 42.1;; MS (+)-LRESI m/z (%) 307 (75) [M
+ Na]+; MS (+)-HRESI calcd. for C12H12N4OF3 [M + H]+ 285.0958, found
285.0964; νmax 2234, 1665, 1613, 1124 cm-1.
[1,4'-Bipiperidin]-1'-yl(1H-imidazol-1-yl)methanone (1g): A solution
of CDI (1.05 g, 6.51 mmol) in anhydrous THF (20 mL) was treated with
4-piperidinopiperidine (1.00 g, 5.96 mmol) under an atmosphere of nitro-
gen. The reaction mixture was then held at reflux for 18 h then cooled to
23 °C and quenched with NaHCO3 (20 mL, saturated aqueous solution)
and extracted with DCM (3 × 20 mL). The combined organic layers were
then washed with water (2 × 20 mL), dried (Na2SO4) and concentrated in
vacuo to afford 1g (1.21 g, 78%) as pale-yellow oil which was used with-
out further purification: 1H NMR (CDCl3, 400 MHz) δ 7.84 (s, 1H), 7.18 (s,
1H), 7.08 (s, 1H), 4.21 – 4.08 (m, 2H), 3.08 – 2.96 (m, 2H), 2.57 – 2.44
(m, 5H), 1.96 – 1.88 (m, 2H), 1.65 – 1.52 (m, 6H), 1.49 – 1.39 (m, 2H);
13C NMR (CDCl3, 100 MHz) δ 13C NMR (CDCl3, 100 MHz) δ 150.8, 136.9,
129.7, 118.0, 62.0, 50.4, 46.3, 28.3, 26.4, 24.8; MS (+)-LRESI m/z (%)
(4-Ethylpiperazin-1-yl)(1H-imidazol-1-yl)methanone (1j). A solution
of CDI (1.56 g, 9.59 mmol) in anhydrous THF (20 mL) was treated with
1-ethylpiperazine (1.10 mL, 8.70 mmol) under an atmosphere of nitrogen.
The reaction mixture was then held at reflux for 18 h then cooled to 23 °C
and quenched with NaHCO3 (20 mL, saturated aqueous solution) and
extracted with DCM (3 × 20 mL). The combined organic layers were then
6
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201700974
European Journal of Organic Chemistry
1
washed with water (2 × 20 mL), dried (Na2SO4) and concentrated in
vacuo to afford 1j (0.98 g, 54%) as yellow oil which was used without
further purification: 1H NMR (CDCl3, 400 MHz) δ 7.86 (s, 1H), 7.19 (br t,
J = 1.4 Hz, 1H), 7.10 – 7.07 (m, 1H), 3.66 – 3.59 (m, 4H), 2.52 – 2.49
(m,4H), 2.46 (q, J = 7.3 Hz, 2H), 1.09 (t, J = 7.2 Hz, 3H); 13C NMR (CDCl3,
100 MHz) δ 150.9, 137.0, 129.9, 118.0, 52.5 (2C), 52.3, 46.6 (2C), 12.0;
MS (+)-LRESI m/z (%) 209 (90) [M + H]+, 141 (100); MS (+)-HRESI calcd.
for C10H17N4O [M + H]+ 209.1397, found 209.1400; νmax 1693, 1429,
1243, 997 cm-1.
g 85 %) as white crystals: mp 54 – 56 °C; H NMR (CDCl3, 500 MHz) δ
7.86 (s, 1H), 7.21 (t, J = 1.3 Hz, 1H), 7.07 – 7.03 (m, 1H), 3.08 (s, 7H);
13C NMR (CDCl3, 125MHz) δ 151.9, 137.0, 129.6, 118.1, 38.5; MS (+)-
LRESI m/z (%) 140 (100) [M + H]+; MS (+)-HRESI calcd. for C6H10N3O
[M + H]+ 140.0824 found 140.0826; νmax 3397, 3119, 2937, 1692, 1396,
1221 cm-1.
Dimethylcarbamoyl cyanide (2m): Prepared according to General
Procedure C [140 °C, 1 h, ramp time 5 minutes, 200 W, PowerMax (cool-
ing with N2(g))] from 1m (139 mg, 1.00 mmol) and TMSCN (131 µL, 1.05
mmol) to afford, after flash chromatography (1:2 Et2O:pentane) 2m (90
mg, 92%) as a yellow oil: 1H NMR (CDCl3, 400 MHz) δ 3.29 (s, 3H), 3.02
(s, 3H).13C NMR (CDCl3, 100 MHz) δ 144.8, 110.6, 37.9, 34.4; MS (+)-
LREI m/z (%) 98 (M+•, 6%), 83 (5), 58 (100); MS (+)-HREI calcd. for
C3H3N2O2 [M-CH3]+• : 83.0240; found, 83.0245; νmax 2939, 2234, 1675,
1491,1439, 1398 cm-1.
4-Ethylpiperazine-1-carbonyl cyanide (2j): Prepared according to
General Procedure C [140 °C, 1 h, ramp time 5 minutes, 200 W,
PowerMax (cooling with N2(g))] from 1j (194 mg, 0.93 mmol) and and
TMSCN (122 µL, 0.98 mmol) to afford, after flash chromatography (1:2,
EtOAc:40-60 petroleum ether), 2j (120 mg, 72%) as a yellow oil: 1H NMR
(CDCl3, 500 MHz) δ 3.75 – 3.73 (m, 2H), 3.63 – 3.61 (m, 2H), 2.52 – 2.50
(m, 2H), 2.44 (q, J = 7.2 Hz, 2H), 2.43 – 2.42 (m, 2H), 1.06 (t, J = 7.2 Hz,
3H); 13C NMR (CDCl3, 125 MHz) δ 143.2, 110.3, 52.6, 52.0, 51.6, 47.1,
42.4, 11.9; GC/MS EI m/z (%) 167 (27, M+•), 152 (100), 138 (13), 123 (8),
113 (22), 98 (12), 84 (10), 70 (7), 56 (33), 42 (40); MS (+)-HRESI calcd.
for C8H14N3O [M + H]+ 168.1131, found 168.1136; νmax 2972, 2815, 2230,
1671, 1447, 1436, 1276, 1246, 1018 cm-1.
N-Methyl-N-(prop-2-yn-1-yl)-1H-imidazole-1-carboxamide (1n): A
vigorously stirring solution of CDI (3.73 g, 23.0 mmol) in DCM (60 mL) at
0 °C under an atmosphere of nitrogen was treated with N-methylpropar-
gyl amine (1.66 mL, 20.0 mmol) portion-wise, followed by dropwise addi-
tion of triethylamine (2.79 mL, 20.0 mmol). The mixture was stirred for 1
h at 0 °C and then stirred for 18 h at 23 °C. The mixture was transferred
to a separatory funnel, diluted with DCM (50 mL) and washed with water
(3 × 30 mL) then brine (25 mL). The organic layer was dried (Na2SO4)
and concentrated in vacuo to afford 1n (2.15 g, 66%) as a tan solid that
was used without further purification: mp 65 – 67 °C; 1H NMR (CDCl3,
400 MHz) δ 7.98 (app. t, J = 1.0 Hz, 1H), 7.32 (app. t, J = 1.6 Hz, 1H),
7.10 (dd, J = 1.6, 1.0 Hz, 1H), 4.18 (d, J = 2.5 Hz, 2H), 3.18 (s, 3H), 2.42
(t, J = 2.5 Hz, 1H); 13C NMR (CDCl3, 100 MHz) δ 151.4, 137.1, 129.9,
118.0, 77.2, 74.1, 40.3, 36.1; MS (+)-LREI m/z (%) 163 (23, M+•), 106
(20), 96 (100), 68 (18), 55 (41); MS (+)-HRESI calcd. for C8H10N3 O [M +
H]+ 164.0818, found 164.0819; νmax 3197, 3140, 2113, 1685, 1274, 1015
cm-1.
(3,4-Dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)(1H-imidazol-1-
yl)methanone (1k): Prepared according to General Procedure A(i) from
1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine (1.22 g, 10 mmol) to afford, after
filtration, the 1k (1.32 g, 61%) as a beige powder: mp 106 – 108 °C; 1H
NMR (CDCl3, 400 MHz) δ 7.95 (s, 1H), 7.28 – 7.27 (m, 1H), 7.15 (s, 1H),
6.67 (t, J = 2.1 Hz, 1H), 6.21 (t, J = 3.1 Hz, 1H), 5.97 – 5.95 (m, 1H), 4.83
(s, 2H), 4.19 – 4.15 (m, 2H), 4.03 – 3.99 (m, 2H); 13C NMR (CDCl3, 100
MHz) δ 151.2, 137.0, 130.2, 123.0, 119.8, 118.0, 109.0, 104.3, 45.4, 44.4,
44.0; MS (+)-LRESI m/z (%) 217 (15) [M + H]+, 149 (100); MS (+)-HRESI
calcd. for C11H13N4O [M + H]+ 217.1084, found 217.1082; νmax 3115,
1693, 1422, 1236 cm-1.
3,4-Dihydropyrrolo[1,2-a]pyrazine-2(1H)-1-carbonyl cyanide (2k):
Prepared according to General Procedure C [140 °C, 1 h, ramp time 5
minutes, 200 W, PowerMax (cooling with N2(g))] from 1k (216 mg, 1.00
mmol) and TMSCN (131 µL, 1.05 mmol) to afford, after flash chromatog-
raphy (1:2, EtOAc:40-60 petroleum ether), 2k (143 mg, 82%) as a tan
powder: mp 110 – 111 °C; 1H NMR (CDCl3, 500 MHz) 1:1 mixture of ro-
tamers δ 6.64 (dd, J = 4.0, 2.2 Hz, 2H), 6.20 (dd, J = 6.5, 3.6 Hz, 2H),
6.05 – 6.03 (m, 1H), 6.05 – 6.03 (m, 1H) 6.01 – 5.98 (m, 1H), 4.98 (s,
2H), 4.80 (s, 2H), 4.14 (s, 4H), 4.07 – 4.04 (m, 2H), 4.02 – 3.99 (m, 2H).
13C NMR (CDCl3, 125 MHz) mixture of rotamers δ 143.8, 143.6, 121.9,
121.6, 120.1, 119.8, 110.2, 110.1, 109.3, 109.2, 104.9, 104.8, 45.1, 44.8,
44.6, 43.5, 41.1, 40.8; GC/MS EI m/z (%) 175 (100, M+•), 146 (4), 121
(38), 106 (32), 93 (39), 80 (9); MS (+)-HRESI calcd. for C9H9N3NaO [M +
Na]+ 198.0638, found 198.0640; νmax 2232, 1664, 1078 cm-1.
Methyl(prop-2-yn-1-yl)carbamoyl cyanide (2n): Prepared according
to General Procedure C [140 °C, 1 h, ramp time 5 minutes, 200 W,
PowerMax (cooling with N2(g)) from 1n (163 mg, 1.00 mmol)] and TMSCN
(131 µL, 1.05 mmol) to afford, after flash chromatography (1:2, EtOAc:40-
60 petroleum ether) 2n (85 mg, 70%) as a yellow oil: 1H NMR (CDCl3,
500 MHz) 0.6:1 mixture of rotamers δ 4.36 (d, J = 2.5 Hz, 2Hmin), 4.21 (d,
J = 2.5 Hz, 2Hmaj), 3.32 (s, 3Hmaj), 3.05 (s, 3Hmin), 2.45 (t, J = 2.5 Hz,
1Hmin), 2.34 (t, J = 2.5 Hz, 1Hmaj); 13C NMR (CDCl3, 125 MHz) major ro-
tamer δ 144.7, 110.2, 75.6, 74.1, 35.9, 35.2; 13C NMR (CDCl3, 125 MHz)
minor rotamer δ 144.3, 110.1, 75.5, 75.0, 40.5, 32.2; MS (+)-HRESI
calcd. for C6H6N2NaO [M + Na]+ 145.0372, found 145.0372; νmax 3291,
2235, 2127, 1690, 1405, 1120 cm-1.
Azetidin-1-yl(1H-imidazol-1-yl)methanone (1o): Prepared accord-
ing to General Procedure B from azetidine hydrochloride (936 mg, 10.0
mmol), CDI (1.78 g, 11.0 mmol), DMF (3 mL) and acetonitrile (10 mL) to
afford, after flash chromatography (1:20, MeOH:DCM), 1o (845 mg 56 %)
as a white crystals: mp 115 – 118 °C; 1H NMR (CDCl3, 500 MHz) δ 7.98
(s, 1H), 7.29 (app. t, J = 1.5 Hz, 1H), 7.09 – 7.05 (m, 1H), 4.34 (app. t, J
= 7.9 Hz, 4H), 2.48 – 2.41 (m, 2H); 13C NMR (CDCl3, 125 MHz) δ 150.3,
136.3, 130.0, 116.7, 51.8 (br, 2C), 16.3; MS (+)-LREI m/z (%) 151 (50,
M+•), 84 (81), 56 (100); MS (+)-HRESI calcd. for C7H10N3O [M + Na]+
152.0818, found 152.0824; νmax 3152, 1668, 1460, 1440, 1224 cm-1.
N-Methyl-N-phenyl-1H-imidazole-1-carboxamide (1l): Prepared ac-
cording to General Procedure A(ii) from N-methylaniline (2.00 g, 18.7
mmol) and CDI (3.94 g, 24.3 mmol) to afford, after flash chromatography
(1:20, MeOH:DCM), 1l (1.30 g, 35%) as a yellow powder: 1H NMR
(CDCl3, 400 MHz) δ 7.57 – 7.52 (m, 1H), 7.41 – 7.27 (m, 3H), 7.13 – 7.09
(m, 2H) 6.84 – 6.82 (m, 1H), 6.79 – 6.78 (m, 1H), 3.47 (s, 3H). Spectral
data were consistent with those reported.23
Methyl(phenyl)carbamoyl cyanide (2l): Prepared according to Gen-
eral Procedure C [140 °C, 1 h, ramp time 5 minutes, 200 W, PowerMax
(cooling with N2(g))] from 1l (201 mg, 1.00 mmol) and TMSCN (131 µL,
1.05 mmol) to afford, after flash chromatography (1:2, EtOAc:40-60 pe-
troleum ether) 2l (135 mg, 84%) as a yellow powder: 1H NMR (CDCl3,
400 MHz) δ 7.35 – 7.18 (m, 3H), 7.19 – 6.97 (m, 2H), 3.13 (s, 3H). Spec-
tral data were consistent with those reported.12
Azetidine-1-carbonyl cyanide (2o): Prepared according to General
Procedure C [100 °C, 2h, ramp time 5 minutes, 200 W, PowerMax (cool-
ing with N2(g))] from 1o (300 mg, 2.00 mmol) and TMSCN (263 µL, 2.10
mmol) to afford, after flash chromatography (1:2 Et2O:pentane) 2o (210
mg, 95%) as a pale-yellow oil: 1H NMR (CDCl3, 500 MHz) 4.40 – 4.36 (m,
2H), 4.15 – 4.11 (m, 2H), 2.48 – 2.41 (m, 2H); 13C NMR (CDCl3, 125 MHz)
δ 143.6, 109.8, 50.7, 49.2, 16.0; MS (+)-LREI m/z (%) 110 (90 M+•), 84
(45), 83 (46), 56 (68), 54 (100); MS (+)-HRESI calcd. for C5H6N2NaO [M
+ Na]+ 133.0372, found 133.0374; νmax 2958, 2231, 1686, 1440, 1298,
922 cm-1.
N,N-Dimethyl-1H-imidazole-1-carboxamide (1m): Prepared accord-
ing to General Procedure B from dimethylamine hydrochloride (1.50 g,
18.4 mmol), CDI (3.28 g, 20.2 mmol), DMF (4 mL) and acetonitrile (15
mL) to afford, after flash chromatography (1:20, MeOH:DCM), 1m (2.18
7
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201700974
European Journal of Organic Chemistry
N-(Cuban-1-ylmethyl)-1H-imidazole-1-carboxamide (1p):. A solu-
tion of cubane carboxylic acid24 (440 mg, 2.97 mmol) in THF (10 mL) was
treated with CDI (578 mg, 3.56 mmol) and the resulting mixture was
stirred at 20 °C for 2 h. The reaction mixture was cooled to 0 °C and
treated dropwise with a solution of methylamine in THF (5.20 mL, 2M).
The resulting mixture was maintained at to 0 °C for a further 0.25 h then
stirred at 20 °C for 16 h. The solvent was removed in vacuo and the res-
idue was subjected to flash column chromatography (silica, 1:9, methanol
saturated with NH3(g):DCM) to give, after concentration of the appropriate
fractions N-methylcubane-1-carboxamide (400 mg, 84%) as a white solid:
mp 162 − 163 °C; 1H NMR (DMSO-d6, 400 MHz) δ 7.57 (br s, H), 4.14 –
4.10 (m, 3H), 3.99 – 3.94 (m, 1H), 3.93 – 3.89 (m, 3H), 2.58 (d, J = 4.6
Hz, 3H); 13C NMR (DMSO-d6, 100 MHz) δ 171.4, 56.9, 48.5, 46.9, 43.7,
25.3; MS (+)-LRESI m/z (%) 184 (100) [M + Na]+, MS (+)-HRESI calcd.
for C10H11NNaO [M + Na]+ 184.0733, found 184.0736; max 3411, 2982,
1618, 1049, 1023, 1001, 823, 761 cm–1. A portion of the N-methylamide
generated above (250 mg, 1.55 mmol) was added to a suspension of
LiAlH4 (294 mg, 7.75 mmol, pellets ground under nitrogen) in THF (30
mL) at 0 °C. After warming to 20 °C the reaction mixture was heated at
reflux for 16 h then cooled to 0 °C and NaSO4.10 H2O (5 g) was cautiously
added portion-wise to quench excess LiAlH4 then vigorously stirred for
0.5 h. The mixture was filtered and the solids were washed with DCM (40
mL). The filtrate was dried (MgSO4) and concentrated in vacuo to afford
a brown oil which was then suspended in water (5 mL), vigorously stirred
and treated portion-wise with CDI (302 mg, 1.86 mmol) at 0 °C. The sus-
pension was then warmed to 20 °C followed by extraction with Et2O (3 ×
10 mL). The combined organic phases were dried (MgSO4) and concen-
trated in vacuo to afford a residue which was purified by flash chromatog-
raphy (3:97, MeOH saturated with NH3(g):DCM) to afford N-(cuban-1-
ylmethyl)-1H-imidazole-1-carboxamide (1p) (200 mg, 53%) as a white
powder: mp 77 − 79 °C; 1H NMR (CDCl3, 400 MHz) δ 7.85 – 7.84 (m, 1H),
7.20 – 7.18 (m, 1H), 7.06 – 7.05 (m, 1H), 4.05 – 3.99 (m, 1H), 3.96 – 3.91
(m, 3H), 3.89 – 3.85 (m, 3H), 3.67 (s, 2H), 3.05 (s, 3H); 13C NMR (CDCl3,
100 MHz) δ 151.9, 137.0, 129.6, 118.2, 57.0, 52.3, 48.4, 48.3, 44.5, 37.2;
MS (+)-LRESI m/z (%) 264 (100) [M + Na]+; MS (+)-HRESI calcd. for
C14H16N3O [M + H]+ 242.1288, found 242.1295; max 2973, 1683, 1476,
1,3-Dibenzyl-5-iminoimidazolidine-2,4-dione (3): Prepared accord-
ing to General Procedure D (10 mins, 100 °C) from 1q (201 mg, 1.00
mmol) and TMSCN (132 µL, 1.05 mmol). Crude product was purified by
flash chromatography (1:30, MeOH:DCM) which afforded three fractions,
A, B and C. Concentration of fraction A afforded 1,3-dibenzyl-5-iminoim-
idazolidine-2,4-dione (3) (63 mg, 44%) as a white powder: mp 141 – 144
°C; 1H NMR (CDCl3, 400 MHz) δ 8.90 (s, 1H), 7.43 – 7.37 (m, 4H), 7.36
– 7.29 (m, 6H), 4.86 (s, 2H), 4.74 (s, 2H); 13C NMR (CDCl3, 100 MHz) δ
156.1, 154.3, 152.4, 135.5, 135.0, 129.0, 128.9, 128.9, 128.9, 128.5,
128.3, 43.3, 43.0; MS (+)-LRESI m/z (%) 316 (100) [M + Na]+; MS (+)-
HRESI calcd. for C17H16N3O2 [M + H]+ 294.1237, found 294.1242; νmax
3258, 1789, 1729, 1671, 1440, 1410, 1136 cm-1. Concentration of fraction
B afforded benzylcarbamoyl cyanide (2q) (38 mg, 24%) as a white pow-
der. Spectral data were identical to those described above. Concentration
of fraction C afforded N-benzyl-1H-imidazole-1-carboxamide (1q) (30
mg, 15%) as a white powder. Spectral data were identical to those de-
scribed above.
N-(4-Methoxybenzyl)-1H-imidazole-1-carboxamide (1r): Prepared
according to General Procedure A(ii) from 4-methoxybenzyl amine (1.30
mL, 10 mmol) and CDI (2.20 g, 13.5 mmol) to afford, after flash chroma-
tography (1:1, acetone:40-60 petroleum ether), 1r (1.05 g, 44%) as a col-
orless solid: 1H NMR (CDCl3, 400 MHz) δ 8.06 – 8.05 (m, 1H), 7.40 –
7.39 (m, 1H), 7.35 (t, J = 5.5 Hz, 1H), 7.26 – 7.22 (m, 2H), 6.92 – 6.91
(m, 1H), 6.88 – 6.84 (m, 2H), 4.49 (d, J = 5.5 Hz, 2H), 3.78 (s, 3H). Spec-
tral data were consistent with those reported.21
(4-Methoxybenzyl)carbmoyl cyanide (2r): Prepared according to
General Procedure D (3 mins, 70 °C) from 1r (261 mg, 1.00 mmol) and
TMSCN (251 µL, 2.00 mmol). The crude product was purified by flash
chromatography (1:20, MeOH:DCM) to afford 2r (180 mg, 94%) as a
pale-yellow solid: 1H NMR (CDCl3, 400 MHz) 1:10 mixture of rotamers δ
7.25 – 7.16 (m, 2H), 6.94 – 6.85 (m, 2H), 6.53 (br s, 1Hmaj), 6.25 (br s,
1Hmin), 4.60 (d, J = 6.5 Hz, 2Hmin), 4.43 (d, J = 5.7 Hz, 2Hmaj), 3.82 (s,
3Hmin), 3.81 (s, 3Hmaj). Spectral data were consistent with those reported.9
N-(2,4-Dimethoxybenzyl)-1H-imidazole-1-carboxamide (1s): Pre-
pared according to General Procedure A(i) from 2,4-dimethoxybenzyl
amine (2.03 g, 10.0 mmol) and CDI (3.24 g, 20 mmol) to afford, after
filtration, 1s (2.29 g, 88%) as a white powder: mp 111 – 114 °C; 1H NMR
(CDCl3, 400 MHz) δ 8.04 – 8.02 (m, 1H), 7.32 – 7.29 (m, 1H), 7.23 (d, J
= 8.1 Hz, 1H), 7.06 – 7.01 (m, 1H), 6.50 – 6.39 (m, 3H), 4.50 (d, J = 5.7
Hz, 2H), 3.85 (s, 3H), 3.80 (s, 3H); 13C NMR (CDCl3,100 MHz) δ 161.2,
158.7, 148.8, 136.0, 131.0, 130.6, 117.5, 115.9, 104.3, 99.0, 55.6, 55.6,
40.9; MS (+)-LRESI m/z (%) 284 (100) [M + Na]+; MS (+)-HRESI calcd.
for C13H15N3O3Na [M + Na]+ 284.1006, found 284.1010; νmax 1718, 1509,
1286, 1130 cm-1.
1216, cm–1
.
N-(Cuban-1-ylmethyl)-1H-imidazole-1-cyanoformamide (2p): Pre-
pared according to General Procedure C [(100 °C, 2 h, ramp time 5
minutes, 200 W, PowerMax (cooling with N2(g))] from 1p (60 mg, 0.25
mmol) and TMSCN (33 µL, 0.26 mmol) to afford, after flash chromatog-
raphy (1:2, Et2O:pentane), 2p (42 mg, 70%) as a pale-yellow oil: 1H NMR
(C6D6, 400 MHz) 2:3 mixture of rotamers δ 3.80 – 3.74 (m, 1Hmin), 3.74 –
3.69 (m, 1Hmaj), 3.65 – 3.61 (m, 3Hmin), 3.59 – 3.55 (m, 3Hmaj), 3.52 – 3.47
(m, 3H); 13C NMR (C6D6, 100 MHz) δ 145.2, 145.0, 111.7, 111.4, 56.8,
56.5, 52.2, 48.6, 48.5, 48.4, 47.9, 44.6, 44.4, 35.9, 33.1; MS (+)-LRESI
m/z (%) 223 (52) [M + Na]+, 413 (100); MS (+)-HRESI calcd. for
C12H12N2NaO [M + Na]+ 223.0842, found 223.0846; νmax 2975, 2231,
1666, 1405, 721 cm-1.
(2,4-Dimethoxybenzyl)carbamoyl cyanide (2s): Prepared according
to General Procedure D (3 mins, 70 °C) from 1s (261 mg, 1.00 mmol) and
TMSCN (251 µL, 2.00 mmol). The crude product was purified by flash
chromatography (1:20, MeOH:DCM) to afford 2s (195 mg, 89%) as a vis-
1
cous colourles oil: H NMR (CDCl3, 400 MHz) 1:9 mixture of rotamers δ
N-Benzyl-1H-imidazole-1-carboxamide (1q): Prepared according to
General Procedure A(i) from benzylamine (1.00 g, 9.33 mmol) and CDI
(1.66 g, 10.3 mmol) to afford, after filtration, 1q (0.91 g, 48%) as a white
powder: mp 66 – 68 °C; 1H NMR (CDCl3, 500 MHz) δ 8.20 – 8.13 (m, 1H),
7.41 – 7.39 (m, 1H), 7.37 – 7.29 (m, 5H), 7.07 (br s, 1H), 7.00 – 6.97 (m,
1H), 4.58 (d, J = 5.7 Hz, 2H). Spectral data were consistent with those
reported.20
7.14 (d, J = 8.2 Hz, 1H), 6.79 – 6.63 (m, NHmaj), 6.48 (d, J = 2.4 Hz, 1H),
6.44 (dd, J = 8.2, 2.4 Hz, 1H), 6.40 (br s, NHmin), 4.54 (d, J = 6.7 Hz,
2Hmin), 4.42 (d, J = 5.9 Hz, 2Hmaj), 3.86 (s, 3Hmaj), 3.85 (s, 3Hmin), 3.81 (s,
3Hmin), 3.81 (s, 3Hmaj);13C NMR (CDCl3,100 MHz) mixture of rotamers δ
161.8min
,
161.5maj
,
158.7maj
,
158.7min
,
145.7maj
,
142.8min
,
131.1min
,
130.4min, 116.4min, 116.1maj, 111.8maj, 110.5min, 104.4maj, 104.3min, 99.0min
,
98.9maj, 55.6maj, 55.5min, 43.8min, 40.4maj; MS (+)-LRESI m/z (%) 243 (100)
[M + Na]+; MS (+)-HRESI calcd. for C11H12N2O3Na [M + Na]+ 243.0740,
found 243.0747; νmax 3267, 2234, 1667, 1616, 1544, 1508, 1212, 1037
cm-1.
Benzylcarbamoyl cyanide (2q): Prepared according to General Pro-
cedure D (3 mins, 70 °C) from 1q (201 mg, 1.00 mmol) and TMSCN (251
µL, 2.00 mmol). Crude product was purified by flash chromatography
(1:30, MeOH:DCM) to afford benzyl cyanoformamide (2q) (133 mg, 83%)
as a white powder: 1H NMR (CDCl3, 400 MHz) 5:95 mixture of rotamers
δ 7.43 – 7.33 (m, 3H), 7.31 – 7.27 (m, 1H), 6.39 (br s, 1Hmaj), 6.18 (br s,
1Hmin), 4.69 (d, J = 6.6 Hz, 2Hmin), 4.52 (d, J = 5.8 Hz, 2Hmaj). Spectral
data were consistent with those reported.9
N-(3,4-Dimethoxyphenethyl)-1H-imidazole-1-carboxamide
(1t):
Prepared according to General Procedure A(i) from 3,4-dimethoxyphene-
thylamine (1.81 g, 10 mmol) and CDI (2.43 g, 15 mmol) to afford, after
filtration, 1t (2.44 g, 88%) as a white powder: mp 135 – 138 °C; 1H NMR
(CDCl3, 400 MHz) δ 8.02 (s, 1H), 7.27 (s, 1H), 7.05 – 6.99 (m, 1H), 6.82
(d, J = 8.0 Hz, 1H), 6.78 – 6.68 (m, 2H), 6.27 (t, J = 5.7 Hz, 1H), 3.86 (s,
8
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201700974
European Journal of Organic Chemistry
3H), 3.83 (s, 3H), 3.69 – 3.62 (m, 2H), 2.89 (t, J = 6.9 Hz, 2H); 13C NMR
(CDCl3, 100 MHz) δ 149.2, 149.1, 147.9, 135.9, 131.0, 129.9, 120.9,
116.3, 112.0, 111.6, 56.0, 55.9, 42.4, 35.1; MS (+)-LRESI m/z (%) 298
(100) [M + Na]+; MS (+)-HRESI calcd. for C14H18N3O3 [M + H]+ 276.1343,
found 276.1348; νmax 3283, 2231, 1701, 1514, 1155, 1023 cm-1.
(m, 1H), 7.38 – 7.35 (m, 1H), 6.92 – 6.88 (m, 1H), 3.28 (td, J = 7.2, 5.6
Hz, 2H), 1.52 – 1.44 (m, 2H), 1.32 – 1.22 (m, 2H), 0.82 (t, J = 7.4 Hz, 3H);
13C NMR (CDCl3, 100 MHz) δ 149.3, 136.1, 129.5, 116.8, 40.9, 31.5,
20.1, 13.7; MS (+)-LREI m/z (%) 167 (5, M+•), 83 (100); MS (+)-HREI
calcd. for C8H13N3O [M]+• 167.1059, found 167.1057; νmax 3288, 2236,
1674, 1544, 1255 cm-1.
(3,4-Dimethoxyphenethyl)carbamoyl cyanide (2t): Prepared ac-
cording to General Procedure D (7 mins, 70 °C) from 1t (275 mg, 1.00
mmol) and TMSCN (251 µL, 2.00 mmol). Crude product was purified by
flash chromatography (1:10, MeOH:DCM) to afford 2t (203 mg, 87%) as
a cream-colored powder: mp 87 – 89 °C; 1H NMR (CDCl3, 400 MHz) 1:9
mixture of rotamers δ 6.84 (d, J = 8.1 Hz, 1H), 6.73 (dd, J = 8.1, 2.1 Hz,
1H), 6.68 (d, J = 2.1 Hz, 1H), 6.19 (br s, 1Hmaj), 5.94 (s, 1Hmin), 3.88 (s,
3H), 3.87 (s, 3H), 3.71 (td, J = 6.7, 6.7 Hz, 2Hmin), 3.60 (td, J = 6.9, 5.9
Hz, 2Hmaj), 2.86 (t, J = 6.62 Hz, 1Hmin) 2.82 (t, J = 6.9 Hz, 2Hmaj). Spectral
data were consistent with those reported.9
n-Butylcarbamoyl cyanide (2w): Prepared according to General Pro-
cedure D (3 mins, 70 °C) from 1w (167 mg, 1.00 mmol) and TMSCN (251
µL, 2.00 mmol). Crude product was purified by flash chromatography
(1:30, MeOH:DCM) to afford 2w (105 mg, 83%) as a colorless oil: 1H
NMR (CDCl3, 400 MHz) δ 6.35 (br s, 1Hmaj), 6.12 (br s, 1Hmin), 3.50 (app.
q, J = 6.9 Hz, 2Hmin), 3.35 (td, J = 7.2, 6.0 Hz, 2Hmaj), 1.65 – 1.60 (m,
2Hmin), 1.60 – 1.51 (m, 2Hmaj), 1.42 – 1.32 (m, 2H), 0.98 (t, J = 7.3 Hz,
3Hmin), 0.94 (t, J = 7.3 Hz, 3Hmaj); 13C NMR (CDCl3, 100 MHz) δ 143.3maj
,
;
111.8maj, 43.3min, 40.5maj, 32.5min, 30.9maj, 20.0maj, 19.7min, 13.7maj, 13.6min
•
MS (+)-LREI m/z (%) 111 (5, M+•−CH3 ), 100 (24, M+•−CN•), 83 (100,
N-(Adamantan-2-yl)-1H-imidazole-1-carboxamide (1u): Prepared
according to General Procedure B from 2-adamantylamine hydrochloride
(1.88 g, 10.0 mmol), CDI (1.78 g, 11.0 mmol), DMF (3 mL) and acetonitrile
(10 mL) to afford, after flash chromatography (1:20, MeOH:DCM), 1u
(1.63 g, 66%) as colorless crystals: mp 145 – 147 °C; 1H NMR (CDCl3,
500 MHz) δ 8.11 – 8.07 (m, 1H), 7.33 – 7.30 (m, 1H), 7.11 – 7.10 (m, 1H),
5.82 (s, 1H), 4.12 (dt, J = 6.8, 3.0 Hz, 1H), 2.10 – 2.04 (m, 2H), 1.96 –
1.85 (m, 6H), 1.83 – 1.71 (m, 6H); 13C NMR (CDCl3, 125 MHz) δ 148.3,
136.0, 130.4, 116.0, 55.6, 37.4, 37.0, 31.9, 31.8, 27.1, 27.0; MS (+)-
LRESI m/z (%) 246 (100) [M + H]+; MS (+)-HRESI calcd. for C14H20N3O
[M + H]+ 246.1601, found 246.1601; νmax 3389, 2906, 1683, 1534 cm-1.
M+•−C3H7 ); MS (+)-HREI calcd. for C5H7N2O [M+•−CH3 ] 111.0558, found
•
•
111.0553; νmax 2237, 1674, 1543, 1255 cm-1.
Acknowledgements
The authors would like to acknowledge Dr Keats Nelms (Beta Thera-
peutics Pty Ltd), Prof. Martin Banwell (The Australian National University)
and Assoc. Profs. Mark Coster and Rohan Davis (Griffith Institute for
Drug Discovery), and Dr Andrew Piggott (Macquarie University) for their
generosity. The authors thank Dr John Tsanaktsidis (CSIRO) and Dr
Justine Walter (Boron Molecular) for provision of 1,4-cubanedicarboxylic
acid and Ellen V. Cliff for assistance with manuscript preparation. BDS is
indebted to The National Health and Medical Research Council for finan-
cial support (grant APP1024314) and JN is grateful to the Australian Gov-
ernment for an APA scholarship.
(Adamantan-2-yl)carbamoyl cyanide (2u): Prepared according to
General Procedure D (5 mins, 70 °C) from 1u (239 mg, 1.00 mmol) and
TMSCN (251 µL, 2.00 mmol). The crude product was purified by flash
chromatography (1:30, MeOH:DCM) to afford 2u (161 mg, 79%) as col-
orless crystals: mp 140 – 144 °C; 1H NMR (CDCl3, 500 MHz) 1:8 mixture
of rotamers δ 6.37 (s, 1H), 4.12 (dt, J = 8.0, 2.6 Hz, 1Hmaj), 4.03 (dt, J =
9.2, 2.8 Hz, 1Hmin), 2.05 – 1.70 (m, 14H); 13C NMR (CDCl3, 100 MHz) δ
13C NMR (CDCl3, 100 MHz) δ 142.5maj, 112.0maj, 111.4min, 58.0min
,
Keywords: cyanoformamide • carbamoyl imidazole • solvent-
55.5maj, 37.3maj, 37.2min, 37.1min, 36.9maj, 33.4min, 31.7maj, 31.5maj, 31.4,
27.0maj, 26.9maj, 26.9min, 26.6min; MS (+)-LREI m/z (%) 204 (31, M+•), 177
(33), 176 (33), 159 (24), 134 (75), 92 (100), 79 (74); MS (+)-HRESI calcd.
for C12H16N2NaO [M + Na]+ 227.1155, found 247.1164; νmax 3293, 2911,
2232, 1664, 1548 cm-1.
free • green chemistry
N-Cyclohexyl-1H-imidazole-1-carboxamide (1v). Prepared accord-
ing to General Procedure A(ii) from cyclohexylamine (1.10 mL, 10.0
mmol) and CDI (2.40 g, 15 mmol) to afford, after flash chromatography
(1:1, acetone:40-60 petroleum ether), 1v (1.40 g, 73%) as a pale-yellow
solid: mp 82 – 83 °C; 1H NMR (CDCl3, 400 MHz) δ 8.10 – 8.08 (m, 1H),
7.32 – 7.29 (m, 1H), 7.11 – 7.08 (m, 1H), 5.63 – 5.40 (m, 1H), 3.89 – 3.78
(m, 1H), 2.10 – 2.03 (m, 2H), 1.82 – 1.74 (m, 2H), 1.72 – 1.64 (m, 1H),
1.48 – 1.36 (m, 2H), 1.32 – 1.17 (m, 3H); 13C NMR (CDCl3, 100 MHz) δ
148.4, 136.1, 129.3, 129.3, 116.7, 50.7, 32.8, 25.3, 25.1; (+)-LRESI m/z
(%) 216 (100) [M + Na]+; MS (+)-HRESI calcd. for C10H15N3ONa [M + Na]+
216.1113 found 216.1107; νmax 3223, 3124, 3029, 2931, 2856, 1697,
1541, 1235 cm-1.
Cyclohexylcarbamoyl cyanide (2v): Prepared according to General
Procedure D (3 mins, 70 °C) from 1v (193 mg, 1.00 mmol) and TMSCN
(251 µL, 2.00 mmol). Crude product was purified by flash chromatog-
raphy (1:20, MeOH:DCM) to afford 2v (113 mg, 74%) as a viscous color-
less oil: 1H NMR (CDCl3, 400 MHz) 1:10 mixture of rotamers δ 6.13 (br s,
1Hmaj), 6.01 (br s, 1Hmin), 3.88 – 3.78 (m, 1Hmaj), 3.78 – 3.69 (m, 1Hmin),
2.00 – 1.90 (m, 2H), 1.82 – 1.70 (m, 2H), 1.68 – 1.60 (m, 1H), 1.44 – 1.31
(m, 2H), 1.30 – 1.14 (m, 3H). νmax 3272, 2934, 2238, 1662, 1559 cm-1.
Spectral data were consistent with those reported.9
n-Butyl-1H-imidazole-1-carboxamide (1w): Prepared according to
General Procedure A(ii) from n-butylamine (496 µL, 5 mmol) and CDI
(1.62 g, 28 mmol) to afford, after extraction, 1w (784 mg, 94%) as a col-
ourless oil: 1H NMR (CDCl3, 400 MHz) δ 8.09 – 8.07 (m, 1H), 7.47 – 7.41
9
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201700974
European Journal of Organic Chemistry
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