2-Cyanopyridazin-3(2H)-ones: Effective and chemoselective electrophilic cyanating agents

Article abstract of DOI:10.1016/j.tet.2005.03.138

2-Cyanopyridazin-3(2H)-ones are novel, effective, selective and electrophilic cyanating agents. A variety of amino, thiol and carbon nucleophiles are chemoselectively N-, S- or C-cyanated in excellent yield using 2-cyanopyridanzin-3(2H)-ones in water or tetrahydrofuran.

Full text of DOI:10.1016/j.tet.2005.03.138

Tetrahedron 61 (2005) 5889–5894
2-Cyanopyridazin-3(2H)-ones: effective and chemoselective
electrophilic cyanating agents
a
a
Jeum-Jong Kim,a Deok-Heon Kweon,a Su-Dong Cho,b, Ho-Kyun Kim, Eun-Young Jung,
*
Sang-Gyeong Lee,c J. R. Falckd and Yong-Jin Yoona,
*
aDepartment of Chemistry and Environmental Biotechnology National Core Research Center, Gyeongsang National University,
Chinju 660-701, South Korea
bDepartment of Chemistry and Research Institute of Basic Science Changwon National University, Changwon 641-773, South Korea
cDepartment of Chemistry and Research Institute of Life Science Gyeongsang National University, Chinju 660-701, South Korea
dDepartment of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
Received 2 March 2005; accepted 29 March 2005
Available online 10 May 2005
Abstract—2-Cyanopyridazin-3(2H)-ones are novel, effective, selective and electrophilic cyanating agents. A variety of amino, thiol and
carbon nucleophiles are chemoselectively N-, S- or C-cyanated in excellent yield using 2-cyanopyridanzin-3(2H)-ones in water or
tetrahydrofuran.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
2. Results and discussion
The introduction of a cyano group via carbon–carbon,
carbon–nitrogen and carbon–sulfur forming reactions is a
fundamental process in organic synthesis. Compounds
containing the N-, S-, or C-cyano functional group are
also found among many pharmaceuticals and their inter-
mediates.1,2 There are a limited number of reagents that can
serve as a cyano cation (CNC) equivalent or synthon, inter
alia, tosyl cyanide,3,4 2-chlorobenzylthiocyanate,5 cyanogen
chloride,6 1-cyanobenzotriazole,7,8 and 1-cyanoimidazole.9
However, problems with poor solubility, lack of reactivity,
cost, stability, corrosiveness, toxicity, complicated
preparation, and/or availability have prompted the con-
tinuing search for a more effective, mild, and convenient
class of electrophilic cyanating agents. Since, pyridazin-
3(2H)-ones 1 readily form stable anions,10 are good leaving
groups, and have been used as a novel synthetic auxiliary.11–14
Our attention focused upon their utility as electrophilic
cyanating agents. Herein, we report the first synthesis and
the application of the hitherto unknown 2-cyanopyridazin-
3(2H)-ones 2 as electrophilic cyanating reagents toward
various amines, sulfur, and carbon nucleophilies.
A variety of 2-cyanopyridazin-3(2H)-ones 2 were readily
prepared by treating the corresponding pyridazin-3(2H)-
ones 1 with cyanogen bromide and triethylamine in
tetrahydrofuran at room temperature (Table 1). Yields
were good to excellent even in the presence of halide,
phenolic, azide, and heteroatom substituents (Scheme 1).
Table 1. Preparation of 2-cyanopyridazin-3(2H)-ones (2)a
Entry
2
Time (h)
Yield (%)b
1
2
3
4
5
6
7
2a
2b
2c
2d
2e
2f
1.2
1.4
1.0
1.0
1.2
1.5
1.3
92
88
85
80
80
83
85
2g
a Compound 1 (1 equiv), BrCN (1 equiv) and Et3N (1 equiv), THF, at room
temperature.
b Isolated yield.
Initially, the efficacy of 2a–g for N-cyanation was evaluated
using N-methylbenzylamine (3a) in water at 15–17 8C
(Table 2, entries 1–7). Among seven N-cyanopyridazin-
3(2H)-ones, 2a and 2b were the best N-cyanating agents.
Consequently, 2a and 2b were further, studied in a variety of
representative organic solvents (entries 8–17). Exclusive
Keywords: N-, S- or C-cyanation; Electrophilic cyanating agent; 2-Cyano-
pyridazin-3(2H)-ones.
*
Corresponding authors. Tel.: C82 055 751 6019; fax: C82 055 761 0244
(S.-D.C); (Y.-J.Y.); e-mail: yjyoon@nongae.gsnu.ac.kr
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.03.138

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J.-J. Kim et al. / Tetrahedron 61 (2005) 5889–5894
selectivity, and long reaction time. Therefore, we chose
tetrahydrofuran as solvent for the a-cyanation of 1,3-
dicarbonyl compounds. Reaction of 2b with b-diketone 3l in
tetrahydrofuran mediated by ZnCl2 or NaH (entries 21 and
22, respectively) gave rise to deacetylated a-cyano ketone 4l
in excellent yields. A similar deacetylation has been
reported.15 On the other hand, deacetylation was not
observed for 3m under identical conditions. Reaction of
3m with 2b (2 equiv) in the presence of ZnCl2 or NaH
(entries 23 and 24, respectively) gave the corresponding
a,a-dicyano derivative 4m in excellent yields, whereas the
use of just 1 equiv of 2b under the same conditions afforded
4m in 46–48% yields. In contrast to the behavior of 2b,
compound 2a was not capable of cyanating the carbon
nucleophiles and yielded 5-substituted-pyridazin-3(2H)-
ones instead of 4l or 4m. Enhancement of the reactivity of
cyano group at N-2 position for the cyanation of N-, S- or
C-nucleophiles with 2 may be due to the chelation of 2 with
zinc chloride (Fig. 1).
Scheme 1.
N-cyanation in good to excellent yields was obtained in
acetonitrile, methanol, and toluene.
Cyanation of various nitrogen and sulfur nucleophiles 3b–h
with 2a–b in water under neutral condition gave the
corresponding N- or S-cyano derivatives 4b–h in good to
excellent yields (Table 3, entries 1–14).
The different product selectivity between substrate 3l and
3m may be due to the different tautomerization of two
substrates under our condition. In order to occur an
intermolecular pyridazinone-mediated deacylation like
Katritzky’s mechanism,15 the terminal acetyl group of 3l
and 3m must be present as a keto-form. Under our reaction
system, the structure (I) of 3l may be more favorable than
the structure (II), whereas the structure (IV) of 3m may be
more favorable than the structure (III) (Scheme 2).
We also investigated the chemoselectivity in the cyanation
of bifunctional nucleophiles such as 4-aminophenol,
4-aminobenzenethiol and 4-mercaptophenol. Firstly,
compounds 3i–k was treated with 2a–b in water to give
both 5-substituted-pyridazin-3(2H)-ones and cyanated 4i–k.
To enhance the chemoselectivity of the cyanation for
bifunctional nucleophiles, we found that the best reaction
condition requires the presence of 1 equiv of zinc chloride
from preliminary experiments. Treatment of bifunctional
nucleophiles 3i–k with 2a,b (entries 15–20) in the presence
of zinc chloride in water chemoselectively afforded N- or
S-cyano derivatives 4i–k in good yields. In order to expand
the applications of the a-cyanation for 1,3-dicarbonyl
compounds, we examined the cyanation of 3l and 3m.
Otherwise the cyanations of N- or S-nucleophile, the
reactions of 1,3-dicarbonyl compounds in water, methanol,
acetonitrile and toluene suffer from low yield, low
3. Conclusion
In conclusion, 2-cyanopyridazin-3(2H)-ones such as 2a and
2b are novel and stable electrophilic cyanating agents. The
methodology presented here, is an efficient, chemoselective,
mild and/or eco-friendly procedure for cyanation of
nitrogen, sulfur and carbon nucleophiles. The solvents
Table 2. Preparation of N-cyano-N-methylbenzylamine (4a) using 2 in various solvents
Entry
2
Solvent
Temp (8C)
Time (h)
4a (%)a
1
2
3
4
5
6
7
8
2a
2b
2c
2d
2e
2f
2g
2a
2b
2a
2b
2a
2b
2a
2b
2a
2b
H2O
H2O
H2O
H2O
H2O
H2O
H2O
CH2Cl2
CH2Cl2
THF
15–17
15–17
15–17
15–17
15–17
15–17
15–17
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
0.5
0.5
1
95
96
88
83
82
85
84
52
41
1
1.2
1.5
1.3
22
28
5
20
9
14
6
9
b
10
11
12
13
14
15
16
17
—
THF
75
88
94
91
89
92
97
CH3CN
CH3CN
MeOH
MeOH
C6H5CH3
C6H5CH3
4
2
2
a Isolated yield. Compound 1 was isolated in good to excellent yields except for entries 1–4 and could be recycled.
b 5-(N-Methyl-N-benzylamino)-4-chloropyridazin-3(2H)-one was obtained in 80% yield.

J.-J. Kim et al. / Tetrahedron 61 (2005) 5889–5894
Table 3. Cyanation of the substrates (3) with 2a–b in water or THF
5891
Entry
2
Substrate (3)
Temp (8C)
Solvent
Time (h)
4 (%)a
1
2
2a
2b
3b
3c
3d
15–17
15–17
H2O
H2O
1.5
0.5
4b (91)
4b (92)
3
4
2a
2b
15–17
15–17
H2O
H2O
1.0
0.5
4c (89)
4c (93)
5
6
2a
2b
15–17
15–17
H2O
H2O
1.2
0.5
4d (84)
4d (86)
7
8
9
10
2a
2b
2a
2b
3e
3f
n-Bu–NH2
15–17
15–17
15–17
15–17
H2O
H2O
H2O
H2O
1.0
0.8
0.8
0.8
n-Bu–NHCN
4e (82)
4e (80)
4f (88)
4f (98)
11
12
2a
2b
3g
3h
3i
15–17
15–17
H2O
H2O
0.5
0.8
4g (82)
4g (78)
13
14
2a
2b
15–17
15–17
H2O
H2O
1.5
1.2
4h (85)
4h (81)
15
16
2a
2b
15–17
15–17
H2O
H2O
1.5
1.5
4i (78)b
4i (85)b
17
18
2a
2b
3j
15–17
15–17
H2O
H2O
1.0
2.1
4j (82)b
4j (85)b
19
20
2a
2b
3k
15–17
15–17
H2O
H2O
1.2
2.0
4k (86)b
4k (85)b
21
22
2b
2b
3l
Reflux
7–8
THF
THF
24
9
4l (93)c
4l (94)d
23
24
2b
2b
3m
Reflux
7–8
THF
THF
14
5
4m (97)e
4m (95)f
a Isolated yield. Compound 1 was isolated in good to excellent yield except for entry 12 and could be recycled.
b Using ZnCl2 (30 mol%) as the catalyst.
c Using ZnCl2 (1 equiv).
d Using NaH (60%, 1.2 equiv).
e Reaction conditions: 2b (2 equiv), ZnCl2 (1 equiv).
Reaction conditions: 2b (2 equiv), NaH (60%, 2.4 equiv).
f

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J.-J. Kim et al. / Tetrahedron 61 (2005) 5889–5894
154.4 ppm. Elemental analysis calcd for C5HCl2N3O: C,
34.52; H, 0.58; N, 24.15; found: C, 34.77; H, 0.53; N, 24.07.
4.2.2. 2-Cyano-4-chloro-5-methoxypyridazin-3(2H)-one
(2b). Yield 88%. Mp 105–106 8C. RfZ0.61 (methylene
chloride). IR (KBr) 3100, 3030, 2980, 2250, 1690, 1600,
1460, 1400, 1300, 1260, 1120, 960 cmK1 1H NMR
;
Figure 1. Chleation of 2 with Zn(II).
(CDCl3): d 4.24 (s, 3H), 8.19 (s, 1H) ppm; 13C NMR
(CDCl3) d 59.1, 105.6, 115.8, 133.8, 155.4, 156.9 ppm.
Elemental analysis calcd for C6H4ClN3O2: C, 38.83; H,
2.17; N, 22.64; found: C, 38.87; H, 2.13; N, 23.46.
4.2.3. 2-Cyano-4-chloro-5-azidopyridazin-3(2H)-one
(2c). Yield 85%. RfZ0.46 (methylene chloride). Mp 114–
115 8C. RfZ0.67. IR (KBr) 3100, 3070, 2250, 2160, 2120,
1700, 1600, 1520, 1380, 1310, 1230, 1130, 1000, 860, 730,
700 cmK1; 1H NMR (CDCl3): d 7.74 (s, 1H) ppm; 13C NMR
(CDCl3) d 105.2, 122.0, 136.3, 140.5, 155.1 ppm. Elemental
analysis calcd for C5HClN6O: C, 30.55; H, 0.51; N, 42.76;
found: C, 30.77; H, 0.53; N, 42.37.
Scheme 2.
4.2.4. 2-Cyano-4-chloro-5-phenoxypyridazin-3(2H)-one
(2d). Yield 80%. RfZ0.42 (methylene chloride). Mp 115–
116 8C. IR (KBr) 3070, 2250, 1720, 1620, 1590, 1540, 1490,
1380, 1280, 1220, 1150, 860, 820, 780, 730, 690 cmK1; 1H
NMR (CDCl3): d 7.12–7.17 (m, 2H), 7.34–7.41 (m, 1H),
7.47–7.55 (m, 2H), 7.65 (s, 1H) ppm; 13C NMR (CDCl3) d
105.4, 118.8, 119.9, 127.2, 130.9, 135.3, 152.7, 153.7,
156.8 ppm. Elemental analysis calcd for C11H6ClN3O2: C,
53.35; H, 2.44; N, 16.97; found: C, 53.57; H, 2.33, N, 16.96.
also affect the reactivity and the selectivity of these systems.
Our investigation of the reactions of these new compounds
is continuing and the results will be reported in due course.
4. Experimental
4.1. General
4.2.5. 2-Cyano-4,5-dibromopyridazin-3(2H)-one (2e).
Yield 80%. RfZ0.62 (methylene chloride). Mp 84–85 8C.
RfZ0.67. IR (KBr) 3080, 3040, 2950, 2260, 1680, 1590,
Melting points were determined with a capillary apparatus
and uncorrected. 1H and 13C NMR spectra were recorded on
a 300 MHz spectrometer with chemical shift values reported
in units (ppm) relative to an internal standard (TMS). IR
spectra were obtained on a IR spectrophotometer. Elemental
analyses were performed with a Perkin Elmer 240C. Open-
bed chromatography was carried out on silica gel (70–230
mesh, Merck) using gravity flow. The column was packed as
slurries with the elution solvent. 4,5-Dichloropyridazin-
3(2H)-one (1a) and 4,5-dibromopyridazin-3(2H)-one (1e)
were prepared by the literature method.16 4-Chloro-5-
substituted-pyridazin-3(2H)-ones 1b–d, 1f and 1g were
prepared from 1a by the reported method.17
1
1510, 1280, 1220, 1110, 960, 860, 720 cmK1; H NMR
(CDCl3): d 7.98 (s, 1H) ppm; 13C NMR (CDCl3) d 137.4,
138.2, 141.1, 142.4, 154.4 ppm. Elemental analysis calcd
for C5HBr2N3O: C, 21.53; H, 0.36; N, 15.07; found: C,
21.71; H, 0.33; N, 15.15.
4.2.6. 2-Cyano-4-chloro-5-(benzylmethylamino)pyrida-
zin-3(2H)-one (2f). Yield 83%. RfZ0.49 (methylene
chloride). Mp 105–106 8C. IR (KBr) 3050, 2980, 2950,
2260, 1690, 1625, 1560, 1500, 1460, 1420, 1360, 1310,
1260, 1240, 1200, 1140, 1100, 1060, 1030, 980, 900, 750,
1
730 cmK1; H NMR (DMSO-d6): d 3.18 (s, 3H), 4.87 (s,
4.2. Synthesis of 2-cyanopyridazin-3(2H)-ones 2
2H), 7.30 (dd, 3H, JZ7.12 Hz, 7.39), 7.39 (dd, 2H, JZ
7.43 Hz, 7.51), 8.27 (s, 1H) ppm; 13C NMR (DMSO-d6) d
41.1, 56.8, 104.6, 107.6, 127.4, 127.9, 129.1, 136.9, 138.9,
147.5, 156.8 ppm. Elemental analysis calcd for
C13H11ClN4O: C, 56.84; H, 4.04; N, 20.40; found: C,
56.87; H, 4.13; N, 20.51.
Triethylamine (0.6 mL, 4.36 mmol) was added slowly to a
stirred solution of 1 (1.1 g, 4.36 mmol) in THF (40 mL) at
room temperature. After stirring 5 min, cyanogen bromide
(4.36 mmol) was added. The reaction mixture was stirred at
room temperature until 1 disappeared. After evaporating the
solvent under reduced pressure, the resulting residue was
applied to the top of an open-bed silica gel column (3.0!
5 cm). The column was eluted with methylene chloride.
Fractions containing 2 were combined and evaporated under
reduced pressure to give 2.
4.2.7. 2-Cyano-4-chloro-5-(phenethylsulfanyl)pyridazin-
3(2H)-one (2g). Yield 85%. RfZ0.51 (methylene chloride).
Mp 141–143 8C. IR (KBr) 3080, 3000, 2950, 2270, 1700,
1590, 1500, 1460, 1440, 1380, 1310, 1290, 1230, 1120, 960,
1
860, 780, 740 cmK1; H NMR (CDCl3): d 3.07 (t, 2H, JZ
4.2.1. 2-Cyano-4,5-dichloropyridazin-3(2H)-one (2a).
Yield 92%. Mp 104–105 8C. RfZ0.56 (methylene chloride).
IR (KBr) 3100, 3050, 2245, 1700, 1600, 1580, 1360, 1260,
7.34 Hz), 3.38 (t, 2H, JZ7.34 Hz), 7.20–7.37 (m, 5H), 7.64
(s, 1H) ppm; 13C NMR (CDCl3) d 33.5, 35.7, 127.6, 128.7,
129.0, 136.9, 137.6, 143.9, 145.2, 152.3, 159.2 ppm.
Elemental analysis calcd for C13H10ClN3OS: C, 53.52; H,
3.45; N, 14.40; found: C, 53.63; H, 3.42; N, 14.50.
1180, 1160, 960 cmK1 1H NMR (CDCl3): d 8.00 (s,
;
1H) ppm; 13C NMR (CDCl3) d 104.9, 134.9, 138.3, 141.2,

J.-J. Kim et al. / Tetrahedron 61 (2005) 5889–5894
5893
4.3. Typical cyanation of nucleophiles in water
D2O exchangable), 7.28–7.36 (m, 5H) ppm. 13C NMR
(CDCl3) d 50.1, 116.3, 127.8, 128.4, 128.9, 136.3 ppm.
Elemental analysis calcd for C8H8N2: C, 72.70; H, 6.10; N,
21.20; found C, 72.81; H, 6.15; N, 21.19.
Nucleophiles (1.2 equiv) was added slowly to a stirred
solution of 2 (200 mg, 1.05 mmol) in water (20 mL) at
15–17 8C. The reaction mixture was stirred at room
temperature until 2 disappeared. The product was extracted
with CH2Cl2 (30 mL!2). The organic layer was dried over
anhydrous magnesium sulfate and then the solvent evapor-
ated under reduced pressure, the resulting residue was
applied to the top of an open-bed silica gel column (3.0!
7 cm). The column was eluted with methylene chloride or
methylene chloride: n-hexaneZ2:1 (v/v); methylene
chloride/etherZ10:1 (v/v). Fractions containing 4 were
combined and evaporated under reduced pressure to give
4 in 78–98% yield.
4.4.5. N-Cyano-n-butylamine (4e). Oil (colorless). RfZ
0.48 (methylene chloride). IR (KBr) 3220, 2970, 2950,
2880, 2220, 1460, 1380, 1360, 1170 cmK1 1H NMR
.
(CDCl3) d 0.92–1.00 (t, 3H, JZ3.36 Hz), 1.34–1.47 (m,
2H), 1.62–1.73 (m, 2H), 2.16 (m, 2H), 3.92 (bs, NH, D2O
exchangable) ppm. 13C NMR (CDCl3) d 13.8, 20.2, 28.8,
44.4, 147.2 ppm. Elemental analysis calcd for C5H10N2: C,
61.19; H, 10.27; N, 28.54; found C, 61.22; H, 10.28; N,
28.49.
4.4.6. (R)-N-Cyano-a-methylbenzylamine (4f). Oil (color-
less). RfZ0.29 (methylene chloride). IR (KBr) 3210, 3000,
4.4. Typical cyanation of 1,3-dicarbonyl compounds in
presence of base or acid
2920, 2230, 1500, 1460, 1380, 1210, 1160, 760, 700 cmK1
.
1H NMR (CDCl3) d 1.53 (d, 3H, JZ6.80 Hz), 4.31 (bs, NH,
D2O exchangable), 4.32–4.41 (m, 1H), 7.25–7.40 (m,
5H) ppm. 13C NMR (CDCl3) d 22.0, 55.6, 115.3, 126.2,
128.3, 128.9, 141.5 ppm. Elemental analysis calcd for
C9H10N2: C, 73.94; H, 6.89; N, 19.16; found C, 73.88; H,
6.91; N, 19.19.
NaH or ZnCl2 (1.1 equiv) was added slowly to a stirred
solution of active methylene (1.08 mmol) in dry-THF
(20 mL) at 7–8 8C (for NaH) and at reflux temperature
(for ZnCl2). After stirring 5 min, 2 (200 mg, 1.08 mmol)
was added. The reaction mixture was refluxed until
carbanion or 2 disappeared. After evaporating the solvent
under reduced pressure, the resulting residue was applied to
the top of an open-bed silica gel column (3.0!10 cm). The
column was eluted with methylene chloride: etherZ
7:1 (v/v). Fractions containing 4l or 4m were combined
and evaporated under reduced pressure to give 4l or 4m in
93–97% yield.
4.4.7. 2-Phenylethyl thiocyanate (4g). Oil (colorless). RfZ
0.50 (methylene chloride). IR (KBr) 3080, 3050, 2950,
2880, 2180, 1610, 1500, 1460, 1330, 1290, 1240, 1080,
1
1040, 760, 710 cmK1. H NMR (CDCl3) d 3.11 (m, 2H),
3.16 (m, 2H), 7.21 (d, 2H, JZ7.00 Hz), 7.27 (dd, 1H, JZ
7.50 Hz), 7.33 (dd, 2H, JZ7.00, 7.50 Hz) ppm. 13C NMR
(CDCl3) d 34.0, 34.9, 110.8, 126.1, 127.5, 127.7,
136.5 ppm. Elemental analysis calcd for C9H9NS: C,
66.22; H, 5.56; N, 8.58; found C, 66.24; H, 5.60; N, 8.56.
4.4.1. N-Cyano-N-methylbenzylamine (4a). Oil (color-
less). RfZ0.70 (methylene chloride/n-hexaneZ2:1 (v/v)).
IR (KBr) 3050, 2950, 2240, 1500, 1460, 1380, 1230, 1160,
1040, 740, 700 cmK1. 1H NMR (CDCl3) d 2.75 (s, 3H), 4.13
(s, 2H), 7.34 (m, 5H) ppm. 13C NMR (CDCl3) d 37.7, 57.1,
118.8, 128.3, 128.5, 128.8, 134.3 ppm. Elemental analysis
calcd for C9H10N2: C, 73.94; H, 6.89; N, 19.16; found C,
73.98; H, 6.84; N, 19.21.
4.4.8. 2-Thiocyanatopyrimidine (4h). Mp 112–113 8C
(colorless). RfZ0.61 (methylene chloride). IR (KBr) 3100,
3000, 2180, 1570, 1390, 1280, 1180, 820, 770, 740, 700,
630 cmK1. 1H NMR (CDCl3) d 7.33 (dd, 1H, JZ4.88 Hz),
8.72 (d, 2H, JZ4.88 Hz) ppm. 13C NMR (CDCl3) d 107.3,
119.7, 158.9, 164.2 ppm. Elemental analysis calcd for
C5H3N3S: C, 43.78; H, 2.20; N, 30.64; found C, 43.91; H,
2.30; N, 29.99.
4.4.2. N-Cyanoaniline (4b). Oil (colorless). RfZ0.43
(methylene chloride/etherZ10:1 (v/v)). IR (KBr) 3190,
3100, 3000, 2930, 2230, 1600, 1500, 1440, 1300, 1250,
750, 690, 490 cmK1. 1H NMR (CDCl3) d 6.19 (s, NH, D2O
exchangable), 6.99 (d, 2H, JZ8.65 Hz), 7.05 (m, 1H), 7.31
(m, 2H) ppm. 13C NMR (CDCl3) d 111.7, 115.5, 123.5,
129.7, 137.4 ppm. Elemental analysis calcd for C7H6N2: C,
71.17; H, 5.12; N, 23.71; found C, 71.21; H, 5.15; N, 23.73.
4.4.9. 4-Thiocyanatoaniline (4i). Mp 55–56 8C (colorless).
RfZ0.23 (methylene chloride). IR (KBr) 3430, 3350, 3250,
3060, 2970, 2930, 2150, 1640, 1600, 1500, 1440, 1300,
1180, 1080, 820, 670, 520 cmK1. 1H NMR (CDCl3) d 3.97
(bs, NH2, D2O exchangeable), 6.64–6.68 (dd, 2H, JZ
6.80 Hz), 7.32–7.36 (dd, 2H, JZ6.86 Hz) ppm. 13C NMR
(CDCl3) d 109.6, 112.3, 116.1, 134.4, 148.9 ppm. Elemental
analysis calcd for C7H6N2S: C, 55.97; H, 4.03; N, 18.65;
found C, 56.01; H, 4.06; N, 18.56.
4.4.3. N-Cyanocyclohexylamine (4c). Oil (colorless). RfZ
0.36 (methylene chloride). IR (KBr) 3200, 2940, 2860,
1
2230, 1450, 1370, 1260, 1170, 1140, 950, 900 cmK1. H
NMR (CDCl3) d 1.98–1.20 (m, 10H), 3.09 (m, 1H), 4.14 (s,
NH, D2O exchangable) ppm. 13C NMR (CDCl3) d 24.3,
25.1, 32.6, 54.4, 115.7 ppm. Elemental analysis calcd for
C7H12N2: C, 67.70; H, 9.74; N, 22.56; found C, 67.75; H,
9.75; N, 22.53.
4.4.10. 4-Thiocyanatophenol (4j). Mp 62–63 8C (color-
less). RfZ0.38 (Ethyl acetate/n-hexaneZ1:3 (v/v)). IR
(KBr) 3400, 2960, 2890, 2180, 1620, 1600, 1500, 1440,
1
1370, 1280, 1240, 1180, 840 cmK1. H NMR (CDCl3) d
6.00 (bs, OH, D2O exchangeable), 6.88 (dd, 2H, JZ
6.50 Hz), 7.44 (dd, 2H, JZ6.50 Hz) ppm. 13C NMR
(CDCl3) d 112.1, 113.4, 117.5, 134.2, 158.0 ppm. Elemental
analysis calcd for C7H5NOS: C, 55.61; H, 3.33; N, 9.26;
found C, 55.68; H, 3.36; N, 9.20.
4.4.4. N-Cyanobenzylamine (4d). Oil (colorless). RfZ0.32
(methylene chloride). IR (KBr) 3260, 3080, 3030, 2220,
1500, 1460, 1440, 1340, 1310, 1220, 1160, 750, 700 cmK1
.
1H NMR (CDCl3) d 4.14 (d, 2H, JZ5.57 Hz), 4.41 (bs, NH,

5894
J.-J. Kim et al. / Tetrahedron 61 (2005) 5889–5894
4.4.11. N-Cyano-4-hydroxyaniline (4k). Mp 218–219 8C
(colorless). RfZ0.41 (ethyl acetate/n-hexaneZ1:2 (v/v)).
IR (KBr) 3200, 2990, 2930, 2230, 1620, 1510, 1440, 1360,
References and notes
1. Gilman, A. G.; Goodman, L. S.; Rall, T. W.; Murad, F.
Goodman and Gilman’s the pharmacological basis of
therapeutics, 7th ed.; Pergamon: New York, 1990; p 899.
2. Hu, L. Y.; Guo, J.; Mager, S. S.; Fischer, J. B.; Burke-Howie,
K. J.; Durant, G. J. J. Med. Chem. 1997, 40, 4281–4289.
3. Kahne, D.; Collum, D. B. Tetrahedron Lett. 1981, 22,
5011–5014.
1
1280, 1260, 1220, 1110, 810, 620, 500 cmK1. H NMR
(DMSO-d6) d 6.77 (m, 4H), 9.17 (bs, NH, D2O exchang-
able), 9.62 (bs, OH, D2O exchangeable) ppm. 13C NMR
(DMSO-d6) d 111.9, 115.1, 115.2, 128.8, 151.8 ppm.
Elemental analysis calcd for C7H6N2O: C, 62.68; H, 4.51;
N, 20.88; found C, 62.60; H, 4.66; N, 20.90.
4. Miyashita, A.; Nakasaki, I.; Kawano, A.; Suzuki, Y.; Iwamoto,
K.-I.; Higashino, T. Heterocycles 1997, 45, 745–755.
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3101–3109.
4.4.12. 2-Cyano-3,4-dihydro-1(2H)-naphthalenone (4l).
Mp 75–77 8C (colorless). RfZ0.76 (methylene chloride/
n-hexaneZ2:1 (v/v)). IR (KBr) 3070, 2950, 2880, 2250,
1700, 1600, 1460, 1440, 1360, 1310, 1230, 1200, 920,
750 cmK1 1H NMR (CDCl3) d 2.43–2.63 (m, 2H),
.
7. Hughes, T. V.; Cava, M. P. J. Org. Chem. 1999, 64, 313–315.
8. Hughes, T. V.; Hammond, S. D.; Cava, M. P. J. Org. Chem.
1998, 63, 401–402.
3.02–3.21 (m, 2H), 3.72–3.78 (dd, 1H, JZ4.60, 4.61 Hz),
7.34–7.40 (dd, 1H, JZ7.74, 7.44 Hz), 7.52–7.59 (m, 1H),
8.05–8.09 (dd, 1H, JZ7.86, 7.89 Hz) ppm. 13C NMR
(CDCl3) d 27.7, 27.8, 40.8, 116.7, 127.5, 128.4, 129.0,
130.5, 134.8, 142.9, 187.8 ppm. Elemental analysis calcd
for C11H9NO: C, 77.17; H, 5.30; N, 8.18; found C, 77.22; H,
5.32; N, 8.09.
9. Wu, Y.-Q.; Limburg, D. C.; Wilkinson, D. E.; Hamilton, G. S.
Org. Lett. 2000, 2, 795–797.
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Heo, J. N. J. Heterocycl. Chem. 1997, 34, 209–214.
11. Kang, Y. J.; Chung, H. A.; Kim, J. J.; Yoon, Y. J. Synthesis
2002, 733–738.
4.4.13. 2,2-Dicyano-1-benzoylacetone (4m). Mp 68–69 8C
(colorless). RfZ0.42 (methylene chloride). IR (KBr) 3070,
2930, 2220, 1735, 1690, 1600, 1550, 1440, 1400, 1360,
1290, 1180, 1020, 990, 860 cmK1. 1H NMR (CDCl3) d 2.54
(s, 3H), 7.48–7.54 (m, 2H), 7.59–7.65 (m, 1H), 8.01–8.05
(m, 2H) ppm. 13C NMR (CDCl3) d 25.6, 88.2, 117.7, 128.6,
128.7, 128.8, 133.1, 133.8, 190.0, 200.2 ppm. Elemental
analysis calcd for C12H8N2O2: C, 67.92; H, 3.80; N, 13.20;
found C, 67.88; H, 3.78; N, 13.16.
12. Kim, J. J.; Park, Y. D.; Lee, W. S.; Cho, S. D.; Yoon, Y. J.
Synthesis 2003, 1517–1520.
13. Park, Y. D.; Kim, H. K.; Kim, J. J.; Cho, S. D.; Kim, S. K.;
Shiro, M.; Yoon, Y. J. J. Org. Chem. 2003, 68, 9113–9115.
14. Kim, J. J.; Park, Y. D.; Kweon, D. H.; Kang, Y. J.; Kim, H. K.;
Lee, S. G.; Cho, S. D.; Lee, W. S.; Yoon, Y. J. Bull. Korean
Chem. Soc. 2004, 25, 501–505.
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C. D.; Akhmedov, N. G. J. Org. Chem. 2004, 69(20),
6617–6622.
Acknowledgements
16. Dury, K. Angew. Chem., Int. Ed. Engl. 1965, 4, 292–300.
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This work was supported by a grant from the Korea Science
and Engineering Foundation (KOSEF) to the Environmental
Biotechnology National Core Research Center (grant #:
R15-2003-012-02001-0).