A new facile method for preparation of heterocyclic α-iminonitriles and α-oxoacetic acid from heterocyclic aldehydes, p-aminophenol, and sodium cyanide

Article abstract of DOI:10.1016/S0040-4039(02)00799-2

Very efficient, simple, and high yield procedures for the transformation of heterocyclic aldehydes into heterocyclic methylidene-p-hydroxyanilines, heterocyclic α-iminonitriles, and finally into heterocyclic α-oxoacetic acids were described. Considering that many of these compounds have biological activity, the synthetic methodology was optimized using readily available, inexpensive starting materials, and the purification of the product involved only simple crystallization.

Full text of DOI:10.1016/S0040-4039(02)00799-2

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 5361–5365
A new facile method for preparation of heterocyclic
a-iminonitriles and a-oxoacetic acid from heterocyclic aldehydes,
p-aminophenol, and sodium cyanide
Branko S. Jursic,* Frederic Douelle, Katherine Bowdy and Edwin D. Stevens
Department of Chemistry, University of New Orleans, New Orleans, LA 70148, USA
Received 29 March 2002; revised 19 April 2002; accepted 23 April 2002
Abstract—Very efficient, simple, and high yield procedures for the transformation of heterocyclic aldehydes into heterocyclic
methylidene-p-hydroxyanilines, heterocyclic a-iminonitriles, and finally into heterocyclic a-oxoacetic acids were described.
Considering that many of these compounds have biological activity, the synthetic methodology was optimized using readily
available, inexpensive starting materials, and the purification of the product involved only simple crystallization. © 2002 Elsevier
Science Ltd. All rights reserved.
Aromatic imines, better known as Schiff bases, can
easily be prepared from corresponding aromatic alde-
hydes and substituted anilines by acid-catalyzed con-
densation in an inert organic solvent.1 Heteroaromatic
imines (Schiff bases) containing the phenol moiety are
of particular interest due to their wide biological prop-
erties, such as antioxidative and anticancer properties.2
They are also precursors for the preparation of other
biologically important compounds. For instance,
reduced and sulfonated heterocyclic Schiff bases have
antiplasmodic activity,3 while acylated Schiff bases
made from heterocyclic aldehydes and p-aminophenol
form liquid crystals.4 Our own preliminary results with
tribarbiturates derived from these valuable intermedi-
ates show promising immune-modulating activity.
Therefore, it is very important to have a simple and
efficient method for the preparation of these com-
pounds. Here we present an exceptionally simple proce-
dure, applicable to multi grams if not to multi kilogram
preparation of these valuable materials. The procedure
involves simple mixing of both the heterocyclic alde-
hyde and p-aminophenol in methanol as a solvent,
refluxing the resulting reaction mixture, and crystalliza-
tion of the solid product from methanol.5 In this way
heterocyclic imines were prepared in high purity and in
almost quantitative yields (Table 1).
a-Iminonitriles as structural derivatives of the men-
tioned Schiff bases also have interesting biological
activities.6 There are many synthetic procedures for the
preparation of aryl(arylimino)acetonitriles but only a
few include heterocyclic aromatic compounds, and the
procedures for preparation are not so simple. For
instance, aromatic amides were converted into a-imi-
Scheme 1. Transformation of heterocyclic aldehyde into heterocyclic a-oxoacetic acid.
Keywords: Schiff bases; a-iminonitriles; a-ketoacids; a-oxoacetic acids; heterocyclic benzylideneanilines.
* Corresponding author.
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)00799-2

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Table 1. The isolated yields (%) of imines (1), a-iminonitriles (3), and a-oxoacetic acids
O
OH
O
H
N
N
H
OH
N
N
N
N
H2N
OH
COOH
CN
DMSO + O2
HCl/H2O
1
3
4
methanol
Heterocycle
Heterocycle
Heterocycle
Heterocycle
The dienamine F oxidizes in air to the final product of
the cyanide-catalyzed imine dimerization G (Scheme 2).
nonitriles through reactions with thionyl chloride fol-
lowed by substitution with copper(I) cyanide.7 These
compounds are also prepared from aromatic aldehydes
through thioethers,8 aldimines,9 a-iminochlorides under
phase-transfer catalysis,10 etc.
One can speculate that by a slight change of the reac-
tion conditions the final outcome of the reaction might
be replacement of the imine hydrogen by the cyanide
group to produce a-iminonitriles. That can be accom-
plished if the production of intermediate D is halted by
protonation of either intermediate B or intermediate C
(Scheme 2). Thus, the secondary amine H produced
should be possible to air oxidize into the corresponding
a-iminonitrile I in the same manner as dienamine F.
Our attempt to control the reaction by slow injection of
acid into the reaction mixture produced a small amount
of the desired product, but the exact procedure was
hard to reproduce. The best results were obtained if the
reaction was performed in weak acid media. Our exper-
iments reveal that phenols with pKa ꢀ10 are the best
acid for this reaction. Even better results are obtained if
phenol is a part of the imine structure.
Considering the structural similarity between Schiff
bases and a-iminonitriles (Scheme 1) one would expect
that simple substitution of the hydrogen of the car-
bonꢀnitrogen double bond (compound 1, Scheme 1)
would result in the preparation of the corresponding
a-iminonitrile. This is actually accomplished through
the addition of cyanogen bromide, followed by elimina-
tion of hydrogen bromide.11 One can envision a similar
reaction path where the addition of hydrogen cyanide is
the first step followed by the elimination of the hydro-
gen molecule via oxidation. There are also some studies
that involve the cyanide anion mediated coupling of
aromatic Schiff bases into the corresponding a,a%-
dianilino derivatives.12 This approach was used for the
preparation of substituted benzyl derivatives13 with lim-
ited application to heterocyclic aromatic diketones.14
According to the proposed mechanism, the cyanide
anion was added to the carbonꢀnitrogen double bond
of the imine, followed by the 1,2-hydrogen shift that
produced a new carbon nucleophile C which adds to
the carbonꢀnitrogen double bond of the second imine
molecule A, generating a new anion D (Scheme 2).
Anion D rearranges into the second carbon nucleophile
E that eliminates the cyanide ion to form dienamine F.
To demonstrate the efficiency of this reaction we have
performed a series of NMR experiments with hetero-
cyclic imines containing the phenolic moiety. Due to its
1H NMR spectra simplicity we selected the reaction
with imine 1c to demonstrate transformation of the
heterocyclic imine into the heterocyclic a-iminonitrile
with a phenolic moiety. The 10 mM DMSO-d6 solution
of 1c was treated with 11 mmol of sodium cyanide and
NMR spectra were recorded every 5 min (Fig. 1). In

B. S. Jursic et al. / Tetrahedron Letters 43 (2002) 5361–5365
5363
Scheme 2. Cyanide anion-promoted oxidative dimerization of Schiff bases.
approximately 30 min at room temperature 1/3 of the
starting material was transformed into secondary amine
2c. After 2 h the reaction was practically completed
(Fig. 1). If the NMR sample is exposed to air for a few
hours then the secondary amine 2c is almost completely
oxidized into a-iminonitrile 3c (Fig. 1). The same
procedure15 was applied for high yield preparation of
additional heterocyclic a-iminonitriles (Table 1).
To fully confirm the structural properties of hetero-
cyclic a-iminonitriles we performed X-ray structural
analysis of the a-iminonitrile prepared from 4-quino-
linecarbaldehyde (Fig. 2). The mono-crystal for the
X-ray analysis was obtained by slow crystallization of
3f from methanol.16 Determined structural properties
agree well with the proposed structure of a-iminoni-
triles. The C(11)ꢀN(12) and the C(19)ꢀN(20) bond dis-
Figure 1. The NMR following the oxidative cyanide addition.
Figure 2. The ORTEP drawing of 3f with one methanol molecule.

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B. S. Jursic et al. / Tetrahedron Letters 43 (2002) 5361–5365
,
tances of 1.2751(15) and 1.1418(15) A, respectively,
indicate the double and triple CꢀN bonds in the a-imi-
nonitriles. Both aromatic moieties (quinoline and phe-
nol) are slightly puckered in regard to the a-iminonitrile
moiety. For instance, the C(3)ꢀC(4)ꢀC(5)ꢀC(6) torsion
angle of the quinoline moiety is 176.77(12)°, while the
same kind of torsion angle of the phenol moiety
C(18)ꢀC(13)ꢀC(14)ꢀC(15) is 3.6(2)°. Both rings form an
angle of ꢀ25° with CꢁN a-iminonitrile moiety.17
filtration, washed with cold methanol (3×25 ml) and dried
at 80°C for a 0.5 h resulting in pure compound in 97%
yield (4.8 g). H NMR (DMSO-d6) l 9.664 (1H, s, OH),
1
8.695 (2H, d, J=6.3 Hz, pyridine 2-H), 8.665 (1H, s,
CHꢁN), 7.791 (2H, d, J=6.0 Hz, pyridine 3-H), 7.283
(2H, d, J=8.7 Hz, phenol 3-H), and 6.820 (2H, d, J=9.0
Hz); 13C NMR (DMSO-d6), 153.784, 151.615, 146.873,
139.545, 138.119, 119.631, 118.417, and 112.356 ppm; MS
(EI) m/z 199 (M+1+, 20%), 198 (M+, 100%), 197 (M−1+,
40%), 120 (M−C5H4N+, 30%), 93 (CH3C5H4N+, 15%),
and 79 (C5H5N, 10%).
a-Iminonitriles are compounds that should be easy to
hydrolyze to the desirable heterocyclic-a-oxoacetic
acids.18 These-a-oxoacetic acids either have biological
activity or they are key intermediates for larger organic
molecules with pharmaceutical or industrial applica-
tions.19 In addition to the hydrolysis of heterocyclic
a-iminonitriles for the formation of a-oxoacetic acids,
there are some other methods of preparation, such as
base hydrolysis of heterocyclic a-oxoamides,20 potas-
sium cyanide and DBU (1,8-diazabicyclo[5.4.0]undec-7-
ene)-catalyzed carbonation of heterocyclic aldehydes,21
a low yield (10–30%) PdCl2(PPh3)2-catalyzed CO car-
bonylation of heterocyclic halides in the presence of
H2O and Et3N.22 Our approach is exceptionally simple,
it involves stirring an aqueous hydrochloric acid sus-
pension of heterocyclic a-iminonitrile followed by the
separation of heterocyclic a-oxoacetic acid from p-
aminophenol.23 The isolated yields are very high (Table
1).
6. Barnikow, G.; Hagen, A.; Hagen, V.; Goeres, E.; Richter,
D.; Fichtner, K. Pharmazie 1983, 38, 449.
7. Jautelat, M.; Ley, K. German Patent DE 2221771, 1973.
8. Pochat, F. Tetrahedron Lett. 1981, 22, 955.
9. Rai, M.; Singh, A. Indian J. Chem., Sect. B 1979, 17, 169.
10. Smith, J. G.; Douglas, C. Synthesis 1978, 894.
11. Rai, M.; Krishan, K.; Singh, A. Indian J. Chem., Sect. B.
1976, 14, 376.
12. Becker, H.-D. J. Org. Chem. 1970, 35, 2099–2102.
13. Walia, J. S.; Singh, J.; Chattha, M. S.; Satyanarayana,
M. Tetrahedron Lett. 1969, 10, 195.
14. Barnes, C. S.; Halbert, E. J.; Goldsack, R. J. Aust. J.
Chem. 1973, 26, 2027.
15. General procedure for preparation of heterocyclic a-imi-
nonitriles. Preparation of (4-hydroxyphenylimino)pyridin-
4-ylacetonitrile (3c).
A dimethyl sulfoxide (100 ml)
solution of 4-(pyridin-4-ylmethyleneamino)phenol (1.98
g; 10 mmol) and sodium cyanide (550 mg; 11 mmol) was
stirred at room temperature for 3 h. The solution imme-
diately turned deep red. The solvent was evaporated at
reduced pressure (0.03 mmHg) with minimal heating
(water bath temperature 40–50°C). A dark red solid
residue was slurred in tetrahydrofuran (100 ml) and
filtered through a short column (6×3 cm) of silica gel. The
silica gel was washed with tetrahydrofuran (6×50 ml). A
combined THF solution was evaporated to solid. The
solid residue was slurred in methanol (50 ml) and the
resulting suspension was heated at 50°C for approxi-
mately 10 min, cooled down in an ice-water bath and the
solid was separated by filtration and washed with ice
cooled methanol (3×20 ml). The product yield was 89%
(1.8 g). 1H NMR (400 MHz, DMSO-d6) l 9.66 (1H,
broad singlet, OH), 8.815 (2H, d, J=6.0 Hz, pyridine
2-H), 7.903 (2H, d, J=6.4 Hz, pyridine 3-H), 7.418 (2H,
d, J=8.8 Hz), and 6.924 ppm (2H, d, J=8.8 Hz). 13C
NMR (400 MHz, DMSO-d6) l 155.336, 147.077, 137.163,
125.610, 120.614, 117.096, 112.355, and 107.983 ppm; MS
(EI) m/z 223 (M+, 20%) and 222 (M−1+, 100%). Anal.
calcd for C13H9N3O: C, 69.95; H, 4.06; N, 18.82. Found:
C, 69.87; H, 18.75; N, 4.13%.
It can be concluded that a very systematic study of the
transformation of heterocyclic aldehydes into hetero-
cyclic Schiff bases, heterocyclic a-iminonitriles, and
finally into heterocyclic a-oxoacetic acid was per-
formed. The resulting synthetic methods are exception-
ally simple, applicable to multi grams if not to multi
kilograms production of industrially and biologically
valuable materials.
References
1. For instance, see: (a) Heinze, K. Chem. Eur. J. 2001, 7,
2922; (b) Gershuns, A. L.; Rastrepina, I. A. Akad. Nauk
SSSR 1969, 17, 242; (c) Unicler, S. R. French Patent FR
2431489, 1981; (d) Atkins, K. J.; Honeybourne, C. L.
Spec. Publ.–R. Soc. Chem. 1991, 91, 121.
2. (a) Bobkova, L. S.; Sharikina, N. I.; Kudryavceva, I. G.;
Ovrucky, V. M.; Choumeiko, V. M.; Kolyadich, O. P.;
Ovrucky, O. V. Farm. Zh. (Kiev) 1997, 79; (b) Hodnett,
E. M.; Mooney, P. D. J. Med. Chem. 1970, 13, 786; (c)
Hodnett, E. M.; Capshew, C. E. Proc. Okla. Acad. Sci.
1970, 49, 105.
16. X-Ray structure determination was performed on Bruker
SMART 1KCCD automated diffractometer. Crystals of
compound 3f were obtained by crystallization from
methanol by allowing slow solvent evaporation. All
reagents and solvents were purchased from Aldrich and
used without prior purification. X-Ray single crystal
structure determination of compound 3f at 155(2) K.
Crystal data: C17H11N3O1 0.744(5) [CH3OH], Mr=
297.08, monoclinic, space group C2/c, a=19.821(2), b=
3. Gaedcke, F.; Knorr, R.; Zymalkowski, F. Arch. Pharm.
1980, 313, 166.
4. Adachi, K. Japanese Patent JP 54005934, 1979.
5. General procedure for preparation of heterocyclic imines.
Preparation of 4-(pyridin-4-ylmethyleneamino)phenol (1).
A mixture of 4-pyridinecarboaldehyde (2.67 g; 25 mmol)
and 4-aminophenol (2.73 g; 2.5 mmol) in methanol (500
ml) was refluxed for 2 h. The solvent was reduced to 1/10
of its original volume. The resulting suspension was
cooled in an ice-water bath. The solid was separated by
,
7.7771(8), c=19.630(2) A, i=105.086(2)°, V=2921.6(5)
3
A , Z=8, zcalcd 1.351 Mg m−3, F000=1243, wavelength
,
−1
,
(u)=0.71073 A, absorption coefficient (v)=0.090 mm
.

B. S. Jursic et al. / Tetrahedron Letters 43 (2002) 5361–5365
5365
Data collection and reduction: crystal size: 0.25×0.55×0.60
mm, theta range: 2.13–33.09°, index ranges: −295h524,
−75k511, −305l530, reflections collected: 13663, inde-
pendent reflections: 5388 [Rint=0.0295], refinement
method: full-matrix least-squares on F2, data/restraints/
parameters: 5388/253/293. Final R indices [I>2|(I)]: R1=
0.0465, wR2=0.1076, goodness-of-fit on F2: 0.815. R
ipenko, T. Ya.; Filits, L. N.; Amel’kin, O. Yu.; Yakhon-
tov, L. N. Khim.-Farm. Zh. 1988, 22, 1087; (e) Cook, M.
C.; Gregory, G. I.; Bradshaw, J. German Patent DE
2265234, 1976.
20. Yamamoto, A.; Ozawa, F.; Takino, H.; Izawa, K.
JapanesePatent JP 60190736, 1985.
21. Haruki, E. Japanese Patent JP 52027745, 1977.
22. Tanaka, M.; Kobayashi, T.; Sakakura, T. German Patent
DE 3605882, 1986.
indices (all data) R1=0.0960, wR2=0.1157, largest diff.
−3
,
peak and hole: 0.416 and −0.311 e A
.
Measurement computing and graphics: SMART 1K CDD
(Bruker, 2000); cell refinement: SMART; data reduction
SAINT-Plus (Bruker, 2000); programs(s) used to solve
structure: SHELXS97 (Sheldrick, 1997); program(s) used
to refine structure: SHELX97 (Sheldrick, 1997); molecu-
lar graphics: SHELXTL97 (Sheldrick, 1997); software
used to prepare material for publication: SHELXTL97.
(a) Bruker (2000). SMART (Version 5.060) and SMART-
Plus (Version 6.02). Bruker AXS Inc., Madison, Wiscon-
sin, USA.
(b) Sheldick, G. M. SHELXTL DOS/Windows/NT. Ver-
sion 5.1. Bruker AXS Inc., Madison, Wisconsin, USA,
1997.
(c) Sheldrick, G. M. SHELXL-97, University of Go¨ttin-
gen, Go¨ttingen, Germany, 1997.
23. General procedure for preparation of heterocyclic a-
oxoacetic acid. Preparation of oxopyridin-3-ylacetic acid
(4b). A hydrochloric acid suspension (5 ml concentrated
HCl plus 5 ml water) of (4-hydroxyphenylimino)pyridin-
3-ylacetonitrile (3b) (450 mg; 2 mmol) was stirred at
room temperature for 2 days. After approximately 1 h
the reaction suspension becomes an orange solution, and
overnight a yellow precipitate was formed. The reaction
mixture was cooled at 0°C for a few hours. The solid,
4-aminophenol, was separated by filtration and water
filtrate was evaporated at reduced pressure followed with
azeotropic benzene (3×20 mL) drying of the solid residue.
The solid residue contains
a small amount of 4-
aminophenol and the product, oxopyridin-3-ylacetic acid
(4b). The solid was heated in methanol (10 ml) with
stirring at 40°C for 15 min, the resulting suspension was
cooled in ice-water bath, separated by filtration and dried
17. For phenol ring this angle is demonstrated by the torsion
angle of 142.77(14)° for C(11)ꢀN(12)ꢀC(13)ꢀC(14) and
for quinoline the comparable torsion angle for
C(3)ꢀC(4)ꢀC(11)ꢀN(12) is 148.33(13)°.
1
at 80°C for 0.5 h to afford 210 mg (70%) of product. H
NMR (DMSO-d6) l 9.144 (1H, d, J=2.1 Hz, pyridine
2-H), 8.907 (1H, dd, J1=5.4 Hz, J2=2.1 Hz, pyridine
6-H), 8.535 (1H, dt, J1=7.8 Hz, J2=2.1 Hz, pyridine
4-H), 7.790 (1H, dd, J1=7.8 Hz, J2=5.4 Hz, pyridine
5-H); 13C NMR (DMSO-d6) l 161.633, 146.560, 143.869,
136.855, 124.432, 121.692, and 96.019 ppm. Anal. calcd
for C7H5NO3: C, 55.63; H, 3.33; N, 9.27. Found: C,
55.79; H, 3.55; N, 9.41%.
18. Masui, M.; Ohmori, H.; Ueda, C.; Yamauchi, M. J.
Chem. Soc., Perkin Trans. 2 1974, 1448.
19. For instance, see: (a) Sadykova, Kh. U.; Abdullaev, A.
Kh. Eksp. Klin. Farmakol. 2001, 64, 57; (b) Brumby, T.;
McDonal, F.; Schneider, H. International Patent WO
012622, 2001; (c) Unterhalt, B.; Gores, P. Arch. Pharm.
1990, 323, 211; (d) Narullaeva, M. K.; Azizov, U. M.;
Azimov, V. A.; Mikhlina, E. E.; Dubinskii, R. A.; Fil-