Pyrolytic methods in organic synthesis: Novel routes for the synthesis of 3-oxoalkanenitriles, 2-acyl anilines, and 2-aroyl anilines

Article abstract of DOI:10.1055/s-2007-992355

3-Oxoalkanenitriles 1a-d were obtained in high yield by treating enaminones 6a-d with hydroxylamine hydrochloride and stirring the resulting oxime with diethyl oxalate. The formed 3-oxoalkanenitriles 1a,b readily undergo self-condensation to yield 2-aroylanilines 3a,b on heating in pyridine for eight hours or by irradiation in microwave for 1.5 minutes. In contrast, 1c-e were recovered unreacted under similar conditions. Pyrolysis of 3-aminocrotononitrile 14 produced a mixture of the aminopyridine 16, 19, and aminobenzene 22. Heating 14 in aqueous media has resulted in formation of the pyridine 20, while heating the same compound in acetic acid has afforded pyridone 20 and acetyl pyridine 24. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2007-992355

LETTER
2979
Pyrolytic Methods in Organic Synthesis: Novel Routes for the Synthesis of
3-Oxoalkanenitriles, 2-Acyl Anilines, and 2-Aroyl Anilines
S
ynthesis of 3-Oxoalkanenitrile
u
s, 2-Acyl
A
n
r
ilines,
a
i
nd 2-
A
a
royl
A
nilines A. Al-Awadi,*a Mervat M. Abdelkhalik,b Ismail A. Abdelhamid,a Mohamed H. Elnagdia
a
Chemistry Department, Faculty of Science, Kuwait University, PO Box 5969, Safat 13060, Kuwait
E-mail: nouria@kuc01.kuniv.edu.kw
b
Applied Science Department, College of Technological Studies, Public Authority for Applied Education and Training,
Safat 13060, Kuwait
Received 23 August 2007
sults of the pyrolytic reactions thermally and under micro-
wave irradiation for the high yield syntheses of 3-
oxoalkane nitriles and 2-aroyl and 2-acylanilines. Al-
though these compounds are already known, synthetic ap-
Abstract: 3-Oxoalkanenitriles 1a–d were obtained in high yield by
treating enaminones 6a–d with hydroxylamine hydrochloride and
stirring the resulting oxime with diethyl oxalate. The formed 3-
oxoalkanenitriles 1a,b readily undergo self-condensation to yield 2-
aroylanilines 3a,b on heating in pyridine for eight hours or by irra- proaches for their derivatives are rather tedious. Elnagdi
et al.9,10 have reported that heating 3-oxo-3-phenylpro-
panenitrile (1a) in pyridine affords 3a (78%) by self-con-
diation in microwave for 1.5 minutes. In contrast, 1c–e were recov-
ered unreacted under similar conditions. Pyrolysis of 3-
aminocrotononitrile 14 produced a mixture of the aminopyridine
densation reaction via intermediacy of 2 (Scheme 1).
16, 19, and aminobenzene 22. Heating 14 in aqueous media has re-
sulted in formation of the pyridine 20, while heating the same com-
However, recently Abdelrazek and Michael11 reported
that the formed product is 4. As 2-aroylanilines are inter-
esting starting materials in synthetic organic chemistry,
we initially checked the structure of this product, and
whether it can be formed in shorter time in absence of sol-
vent in a microwave oven.12–14
pound in acetic acid has afforded pyridone 20 and acetyl pyridine
24.
Key words: microwave heating, aminoacetophenone derivative,
HMBC 15N NMR
We have found that refluxing 1a in pyridine for two hours,
as described by Abdelrazek and Michael,11 has resulted in
low yield of the self-condensation product, most of 1a was
recovered unreacted. Only after eight hours heating, the
self-condensation product could be isolated in good yield.
The 13C NMR showed15 21 carbon signals, while if the re-
action product is 4, only seven carbon signals should have
been revealed. Moreover, MS of this product shows mo-
lecular ion peak at 399; while 4 would reveal molecular
ion peak at 381. Possible formation of 5 was also excluded
Generally, pyrolytic reactions have permitted the straight-
forward synthesis of many organic compounds.1,2 Such
reactions are increasingly being used as atom-efficient
and environmentally desirable pathways to clean func-
tional-group transformation and synthesis of organic
compounds.3–5 We have adopted this approach in efficient
synthesis of nitriles.6–8 Recently, we became interested in
adopting microwave technology as energy source for our
pyrolytic reactions. The present study examines the re-
O
NH2
CN
R
R
O
R
O
pyridine
CN
CN
CN
CN
R
R
3
8 h
1a,b
3
Ph
Ph
1a, R = Ph
NC
Ph
CN
b, R = C6H4(4-Cl)
c, R = thiophen-2-yl
d, R = furan-2-yl
e, R = indol-3-yl
2
X
Ph
O
Ph
CN
CN
Ph
4
H2N
H2O
Ph
CN
5
Scheme 1
SYNLETT 2007, No. 19, pp 2979–2982
x
x
.x
x
.2
0
0
7
Advanced online publication: 08.11.2007
DOI: 10.1055/s-2007-992355; Art ID: G25207ST
© Georg Thieme Verlag Stuttgart · New York

2980
N. A. Al-Awadi et al.
LETTER
based on 13C NMR experiments that revealed carbonyl
carbon at d ~ 186 ppm. Thus the structure of 3 is estab-
lished. To expedite the reaction, we heated 1a,b in a mi-
crowave oven at 200 °C for 1.5 minutes where compound
3 was formed in 85% yield.16 It seems that this self-con-
densation reaction is an excellent route for the synthesis of
2-aroylbenzenes as reported; synthetic routes for this
compound cannot in fact be adopted to enable synthesis of
such polyfunctional derivatives.17 However, a literature
search to the synthetic approaches of 3-
oxoalkanenitrile18,19 indicated that these cannot be readily
adopted for high-yield, low-cost synthesis of targeted
molecules 1a–d. As we had earlier shown that nitriles can
be readily produced via pyrolysis of acylated oximes6,7 we
looked into the possibility of adopting such a route and de-
veloping an easy high-yield approach for the synthesis of
compounds 1a–d. Reacting the enaminones 6a–d20 with
hydroxylamine hydrochloride in ethanolic sodium acetate
at room temperature resulted in formation of a product of
condensation via dimethylamine elimination.21 This prod-
uct was found to exist as an equilibrium mixture, the hy-
O
HO
OH
N
O
N
O
R
NH2OH⋅HCl
R
NaOAc
R
Me
N
8
7
Me
O
O
6a, R = Ph
NaH, dioxane
r.t.
b, R = C6H4(4-Cl)
c, R = thiophen-2-yl
d, R = furan-2-yl
EtO
OEt
9
OEt
O
O
O
O
H
N
O
O
CN
+
R
O:
EtO
OH
R
1a–d
11
10
COOH
Ac2O
+
1e
N
H
CN
13
12
Scheme 2
1
Compound 1e was prepared by following our recent
procedure23 from indole 12, cyanoacetic acid, and acetic
anhydride (cf. Scheme 2).
droxylamino E- and Z-forms (7 or 8) based on H NMR
spectra which revealed two doublets at d = 3.92 and 4.02
ppm for CH2 protons and other two triplets at d = 7.00 and
7.50 ppm for oxime CH. In an attempt to convert 7 or 8
into nitriles, we initially refluxed this oxime with acetic
anhydride. The oxime under these conditions was recov-
ered unreacted. When stirred with diethyl oxalate in diox-
ane in the presence of sodium hydride for two hours, the
oxoalkane nitriles 1a–d were produced.22 It is believed
that 7 is initially converted into 10, which then loses oxal-
ic acid monoethyl ester in a six-membered transition state.
While 1a,b readily underwent self-condensation to yield
3a,b, compounds 1c–e were recovered unaffected when
treated under similar conditions. This could be attributed
to the electron donation to carbonyl carbon by the heteroa-
tom; the carbonyl carbon is not sufficiently electrophilic
to undergo self-condensation. 2-Acyl p-excessive mole-
cules as well as 3-acylindoles are reported to be less reac-
NH2
NH NH2
CN
CN
CN
Me
NH2
Me
Me
pyridine,
8 h
14
CN
Me
17
Me
MW heating for
1.5 min
14
CN
22
H2N
Me
AcOH, NH4OAc
NC
Me
NC
Me
O
NH2
Me
NH2
NH
15
CN
Me
N
H
NH
Me
18
Me
CN
23
NH2
H2O
Me
NC
Me
X
NC
Me
N
Me
Me
NH2
N
NH2
16
NC
Me
CN
NH
19
N
H
O
Me
O
20
21
Scheme 3
Synlett 2007, No. 19, 2979–2982 © Thieme Stuttgart · New York

LETTER
Synthesis of 3-Oxoalkanenitriles, 2-Acyl Anilines, and 2-Aroyl Anilines
2981
tive toward nucleophiles as compared to their aryl
analogues.24
Acknowledgment
This work was supported by Kuwait University through research
grant # Sc08/04 and ANALAB and SAF grants # GS01/01 and
GS04/01. We wish to thank Dr. Y. A. Ibrahim for his assistance
with NMR analysis.
3-Aminocrotononitrile (14) has been dimerized under
various conditions25–27 to yield 16, 19, or 20 depending on
the applied conditions (Scheme 3). We have noticed that
heating 14 in dry pyridine resulted in formation of a mix-
ture of three products of molecular formula C12H12N4 and
C8H9N3, these were separated by column chromatography
using ethyl acetate–petroleum ether in a ratio of 1:4.28 The
product of molecular formula C12H12N4 was assigned to
structure 22. Spectral data of this product are in complete
agreement with the proposed structure. The other two
products of the same molecular formula C8H9N3 were as-
signed to the aminopyridine structures 16 and 19. The
HMBC 15N NMR (60 Hz) enabled distinguishing 16 and
19. As pyridine-ring nitrogen at d = 260 ppm showed a
cross-peak with the amino proton at d = 6.52 ppm. Thus
the structure of 19 was established. It is assumed that both
19 and 22 were produced from the same self-condensation
intermediate 17. This either condenses with one molecule
of 14 to yield 22 or cyclize into 19. On the other hand, 16
is produced via initial addition of methylene group to the
cyano function in 15 and subsequent cyclization. Acyclic
structures were ruled out based on the absence of CH at
d > 6.0 ppm.
References and Notes
(1) Al-Awadi, N.; Abdelhamid, I. A.; Al-Etaibi, A.; Elnagdi, M.
H. Synlett, accepted for publication.
(2) Al-Awadi, N. A.; George, B. J.; Dib, H. H.; Ibrahim, M. R.;
Ibrahim, Y. A.; El-Dusouqui, O. M. Tetrahedron 2005, 61,
8257.
(3) Al-Awadi, H.; Ibrahim, M. R.; Dib, H. H.; Al-Awadi, N. A.;
Ibrahim, A. I. Tetrahedron 2005, 61, 10507.
(4) Al-Awadi, N. A.; Elnagdi, M. H.; Ibrahim, Y. A.; Kaul, K.;
Kumar, A. Tetrahedron 2001, 57, 1609.
(5) Al-Awadi, S. A.; Abdallah, M. R.; Dib, H. H.; Ibrahim, M.
R.; Al-Awadi, N. A.; El-Dusouqui, O. M. E. Tetrahedron
2005, 61, 5769.
(6) El-Dusouqui, O. M. E.; Abdelkhalik, M. M.; Al-Awadi, N.
A.; Dib, H. H.; George, B. J.; Elnagdi, M. H. J. Chem. Res.
2006, 295.
(7) Al-Awadi, N. A.; Ibrahim, Y. A.; Patel, M.; George, B. J.;
Al-Etiabi, A. M. Int. J. Chem. Kinet. 2007, 39, 59.
(8) Al-Awadi, N. A.; Ibrahim, Y.; Kaul, K.; Dib, H. J. Phys.
Org. Chem. 2001, 14, 521.
(9) Elgemeie, G. E. H.; Elfahham, H. A.; Elnagdi, M. H.
Heterocycles 1985, 23, 1999.
(10) Al-Omran, F.; El-Khair, A. A.; Elnagdi, M. H. Org. Prep.
Proced. Int. 1998, 30, 211.
Compound 19 is known and its reported physical data are
in agreement with those obtained in this study.29 The self-
condensation reaction in aqueous medium resulted in for-
mation of a product that was assigned to the 2-pyridone
(11) Abdelrazek, F. M.; Michael, F. A. J. Heterocycl. Chem.
2006, 43, 7.
1
structure 20 based on H NMR that revealed a lowfield
(12) Microwave heating was carried out with a single-mode
cavity explorer microwave synthesizer, CEM Corporation,
NC, USA.
(13) Microwaves in Organic Synthesis; Loupy, A., Ed.; Wiley-
VCH: Weinheim, 2002.
NH resonance at d = 12.82 ppm and 13C NMR that re-
vealed an amide carbonyl at d = 161.6 ppm.30 If the reac-
tion product is the pyranimine 21, one would expect pyran
NH to appear at higher field. Moreover, the reaction prod-
uct was recovered unchanged when refluxed in ethanolic
hydrochloric acid, a condition that is expected to affect ei-
ther hydrolysis of the pyranimine 21 mostly yielding pyr-
anone or at least rearrangement to pyridine. In addition,
15N-HMBC indicated an interaction between the NH sig-
nal and methyl protons. Heating compound 22 in acetic
acid/ammonium acetate resulted in the formation of 23.
Refluxing 14 in acetic acid afforded the pyridone 20 in ad-
dition to acylaminolutidine 24 (Scheme 4).29
(14) (a) Kappe, C. O. Angew. Chem. 2004, 116, 6408.
(b) Kappe, C. O. Angew. Chem. 2004, 43, 6250.
(15) NMR spectra were measured using a Bruker DPX 400 MHz
superconducting spectrometer, 1HMBC-15N and NOE
spectra were measured using Bruker Avance II 600 MHz
superconducting spectrometer, and FT-IR measurements
were performed with a Perkin Elmer 2000 FT-IR system.
Mass spectrometric analysis was carried out on a VG-
Autospec-Q high performance tri-sector GC/MS/MS.
(16) General Method for Preparation of Compounds 3a,b
Method A: Arylacetonitrile (10 mmol) was refluxed in
pyridine (20 mL) for 8 h. The solvent was evaporated under
vacuum, and the solid product was collected by filtration and
crystallized from DMF–EtOH.
Me
Me
NC
Me
NC
Me
Method B: Arylacetonitrile 1a in pyridine (2 mL) was
heated alone for 1.5 min in a microwave oven, the reaction
mixture was then poured on cold H2O. The so-formed solid
product was collected by filtration and crystallized from
EtOH–DMF.
AcOH
+
14
N
NHCOMe
N
H
O
20
24
5¢-Amino-6¢-benzoyl-[1,1¢;3¢,1¢¢]terphenyl-2¢,4¢-
dicarbonitrile (3a)
Scheme 4
Yield 78%; mp 295 °C. MS: m/z (%) = 399(40). IR: 3437
and 3175 (NH2), 2224 and 2199 (2 CN), 1654 (CO) cm–1. 1H
NMR (400 MHz, DMSO): d = 7.52–7.83 (m, 15 H, PhH),
8.01 (br s, 2 H, NH2). 13C NMR (100 MHz, DMSO):
d = 80.0, 100.7, 116.5, 118.2, 119.5, 128.5, 128.6, 128.9,
129, 129.2, 129.6, 130.7, 131.8, 132.0, 133.4,135.9, 137.6,
155.3, 155.8, 157.0, 186.7.
We can conclude that the structures of the self-condensa-
tion of 3-oxoalkanenitriles and 2-aminocrotononitriles are
correctly assigned and we showed that such reactions can
take place readily in a microwave oven. In addition, a new
simple and efficient route to 3-oxoalkanonitriles was re-
ported.
Synlett 2007, No. 19, 2979–2982 © Thieme Stuttgart · New York

2982
N. A. Al-Awadi et al.
LETTER
(17) Elnagdi, M. H.; Elmoghayer, M. R. H.; Elgemeie, G. E. H.
Synthesis 1984, 1.
(18) Lee, S.; Kim, T.; Lee, B. H.; Yoo, S.-e.; Lee, K.; Yi, K. Y.
Bioorg. Med. Chem. Lett. 2007, 17, 1291.
(19) Kamila, S.; Zhu, D.; Biehl, E. R.; Hua, L. Org. Lett. 2006, 8,
4429.
(20) Al-Omran, F.; Abdelkhalik, M. M.; El-Khair, A. A.;
Elnagdi, M. H. Synthesis 91.
(28) General Method for Preparation of Compounds 14, 17,
18, and 20
3-Aminocrotononitrile (10 mmol) was refluxed in pyridine
(20 mL) for 8 h. The solvent was evaporated under vacuum,
and the solid product was collected by filtration. The
mixture of the three compounds was separated by means of
column chromatography on silica gel with EtOAc–PE (1:4)
as eluent.
(21) General Method for Preparation of Compounds 7
A mixture of each of the enaminones 6 (10 mmol),
NH2OH·HCl (20 mmol), and NaOAc (20 mmol) was stirred
in EtOH–H2O mixture for 2 h at r.t. The reaction mixture
was then poured on cold H2O. The so-formed solid product
was collected by filtration and crystallized from EtOH.
3-Oxo-3-thiophen-2-yl-propionaldehyde Oxime (7c)
Yield 78%; mp 118–120 °C. MS: m/z 169. IR: 3197 (OH),
1653 (CO) cm–1. 1H NMR (400 MHz, DMSO): d = 3.92 (d,
2 H, CH2), 4.02 (d, 2 H, CH2), 7.00 (t, 1 H, vinyl-H), 7.26
(dd, 1 H, thiophene H4), 7.50 (t, 1 H, vinyl-H), 8.03 (d, 1 H,
thiophene-H3), 8.05 (d, 1 H, thiophene-H5). 13C NMR (100
MHz, DMSO): d = 36.03, 36.2, 50.5, 52.3, 125.9, 127.02,
127.7, 129.7, 134.8, 135.1, 136.1, 136.2, 143.9, 144.02,
145.3, 148.7, 189.6, 190.5.
(22) General Procedures for Preparation of 1a–d
A mixture of each of the oximes 7 (10 mmol), diethyloxalate
(10 mmol), and NaH (20 mmol) in dioxane (5 mL) was
stirred for 2 h at r.t. The reaction mixture was then
evaporated and triturated with EtOH. The so-formed solid
product was collected by filtration and crystallized from
EtOH.
4-Amino-2,6-dimethylnicotinonitrile (14)
Yield 30%; mp 313 °C. MS: m/z = 148. IR: 3367, 3358
(NH2), 2211 (CN) cm–1. 1H NMR (400 MHz, DMSO):
d = 2.42 (s, 3 H, CH3), 2.60 (s, 3 H, CH3), 7.65 (s, 1 H, vinyl-
H), 10.62 (s, 2 H, NH2). 13C NMR (100 MHz, DMSO):
d = 20.8, 23.6, 101.5, 110.5, 117.5, 152.4, 155.0, 161.2.
6-Amino-2,4-dimethylnicotinonitrile (17)
Yield 32%; mp 230 °C. MS: m/z = 148. IR: 3391, 3336
(NH2), 2212 (CN) cm–1. 1H NMR (400 MHz, DMSO):
d = 2.23 (s, 3 H, CH3), 2.38 (s, 3 H, CH3), 6.20 (s, 1 H, vinyl-
H), 6.82 (br, 2 H, NH2). 13C NMR (100 MHz, DMSO):
d = 20.2, 23.5, 95.5, 105.8, 118.7, 150.5, 161.1, 162.1.
4-Amino-5-(1-iminoethyl)-2,6-dimethylisophthalonitrile
(20)
Yield 27%; mp 302–304 °C. MS: m/z = 212. IR: 3391 (NH),
3330, 3148 (NH2), 2211 (CN), 1662 (C=NH) cm–1. 1H NMR
(400 MHz, DMSO): d = 2.20 (s, 3 H, CH3), 2.38 (s, 3 H,
CH3), 2.68 (s, 3 H, CH3), 6.20 (s, 1 H, vinyl-H), 6.60–6.83
(br, 2 H, NH2) 9.80 (s, 1 H, NH). 13C NMR (100 MHz,
DMSO): d = 20.8, 21.65, 24.2, 75.6, 102.1, 111.3, 117.7,
121, 152.0, 154.6, 156.3, 161.7.
(29) Sato, K.; Ohashi, M. Bull. Chem. Soc. Jpn. 1969, 42, 2319.
(30) 2,4-Dimethyl-6-oxo-1,6-dihydropyridine-3-carbonitrile
(18)
(23) Abdel-Motaleb, R. M.; Makhloof, A. A.; Ibrahim, H. M.;
Elnagdi, M. H. J. Heterocycl. Chem. 2007, 44, 109.
(24) Gilchrist, T. L. Heterocyclic Chemistry, 3rd ed.; Prentice
Hall: New York, 1997, 205.
(25) Holtwart, R. J. Prakt. Chem. 1889, 39, 230.
(26) Moir, J. J. Chem. Soc. 1902, 81, 111.
Yield 42%; mp 295 °C. MS: m/z = 148: IR: 3090 (NH), 2217
(CN), 1659 (CO) cm–1. 1H NMR (400 MHz, DMSO):
d = 2.20 (s, 3 H, CH3), 2.40 (s, 3 H, CH3), 6.16 (s, 1 H, vinyl-
H), 6.82 (br, 1 H, NH). 13C NMR (100 MHz, DMSO):
d = 18.2, 20.1, 90.9, 116.2, 149.5, 150.5, 154.8, 161.6.
(27) Von Meyer, E. J. Prakt. Chem. 1895, 52, 89.
Synlett 2007, No. 19, 2979–2982 © Thieme Stuttgart · New York

Copyright of Synlett is the property of Georg Thieme Verlag Stuttgart and its content may not
be copied or emailed to multiple sites or posted to a listserv without the copyright holder's
express written permission. However, users may print, download, or email articles for
individual use.