Enaminones in organic synthesis: A novel synthesis of 1,3,5-trisubstituted benzene derivatives and of 2-substituted-5-aroylpyridines

Article abstract of DOI:10.1081/SCC-120001996

Enaminones undergo self-condensation on reflux in acidic media yielding 1,3,5-trisubstituted benzene in very high yields. Reaction of enaminones 1a,b with ethyl propiolate affords 5-aroyl-1,3-benzene dicarboxylate derivatives.

Full text of DOI:10.1081/SCC-120001996

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ENAMINONES IN ORGANIC SYNTHESIS: A NOVEL
SYNTHESIS OF 1,3,5-TRISUBSTITUTED BENZENE
DERIVATIVES AND OF 2-SUBSTITUTED-5-
AROYLPYRIDINES
Mervat Mohammed Abdel-Khalik a & Mohamed Hilmy Elnagdi b
a Department of Chemistry , Ain Shams University , Girls College for Arts, Science and
Education, P.O. Box 11757, Heliopolis, Cairo, A. R. Egypt
b Department of Chemistry , Faculty of Science , Cairo University , Giza, A. R. Egypt
Published online: 16 Aug 2006.
To cite this article: Mervat Mohammed Abdel-Khalik & Mohamed Hilmy Elnagdi (2002) ENAMINONES IN ORGANIC
SYNTHESIS: A NOVEL SYNTHESIS OF 1,3,5-TRISUBSTITUTED BENZENE DERIVATIVES AND OF 2-SUBSTITUTED-5-
AROYLPYRIDINES, Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic
Chemistry, 32:2, 159-164, DOI: 10.1081/SCC-120001996
To link to this article: http://dx.doi.org/10.1081/SCC-120001996
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SYNTHETIC COMMUNICATIONS, 32(2), 159–164 (2002)
ENAMINONES IN ORGANIC SYNTHESIS:
A NOVEL SYNTHESIS OF
1,3,5-TRISUBSTITUTED BENZENE
DERIVATIVES AND OF 2-SUBSTITUTED-
5-AROYLPYRIDINES
Mervat Mohammed Abdel-Khalik1 and
Mohamed Hilmy Elnagdi2,
*
1Department of Chemistry, Girls College for Arts,
Science and Education, Ain Shams University,
P.O. Box 11757, Heliopolis, Cairo, A. R. Egypt
2Department of Chemistry, Faculty of Science,
Cairo University, Giza, A. R. Egypt
ABSTRACT
Enaminones undergo self-condensation on reflux in acidic
media yielding 1,3,5-trisubstituted benzene in very high
yields. Reaction of enaminones 1a,b with ethyl propiolate
affords 5-aroyl-1,3-benzene dicarboxylate derivatives.
Enaminones are versatile readily obtainable reagents and their reactiv-
ity toward nucleophiles has in the past received considerable interest.1–3
Although C-2 in enaminones is electron rich, very little has been reported
on reactivity of enaminones toward electrophilic reagents. In previous report
*Corresponding author.
159
Copyright & 2002 by Marcel Dekker, Inc.
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ABDEL-KHALIK AND ELNAGDI
we have investigated the reactivity of enaminones toward aromatic diazo-
nium salts.4–5 In the present article we report results of our work aimed at
exploring reactivity of enaminones toward carbon electrophiles. The work
enabled development of an easy and efficient route to 1,3,5-functionally sub-
stituted benzenes, as well as 2-substituted-5-aroylpyridines derivatives. Thus
the enaminones 1a,b reacted readily with ethyl propiolate to yield a mixture of
three products. The major product (70% yield) of this reaction showed
molecular formula corresponding to condensation of two molecules of the
propiolate with one molecule of each of 1a,b, via loss of dimethylamine. One
of the minor products (15% yield) proved to result from condensation of
three molecules of 1a,b, via elimination of three molecules of dimethylamine.
The third product of this reaction could not however be isolated in pure form
as it was formed in less than 2%. Several isomeric structures for the major
product seemed possible. The 1H NMR and the 13C NMR however enabled
1
ready exclusion of non-symmetrical benzene structures. Thus the H NMR
for compound 4a displayed two proton signal at d ¼ 8.61 ppm and a one
proton signal at d ¼ 8.14 ppm in addition to heteroaroyl multiplets at
d ¼ 7.52–7.53 and 6.80–6.82 ppm together with the ester signals. The signal
at d ¼ 8.61 ppm is coupled with that at d ¼ 8.14 ppm (J ¼ 3 Hz). This small
coupling indicate that the protons are not adjacent to each other in an
aromatic system. In addition the 13C NMR simulated spectra of all possible
isomeric benzene derivatives showed that actual spectra is almost identical
with that of the 1,3,5-trisubstituted derivatives 4 and is different than that of
other possible isomers. The 1H,1H-cosey for compound 4a confirmed further
our conclusion. The 1H NMR and the 13C NMR for compound 4b is similar
to that of 4a. Thus structures 4 was established for the major reaction

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161
product. It is possible to assum that this product is formed via a [2 þ 2 þ 2]
concerted cycloaddition mechanism yielding 3 which loses dimethylamine to
yield 4. However, possible initial formation of intermediate 2 which then adds
further one molecule of ethyl propiolate to yield 3 that aromatize into 4
cannot be ruled out.
1
The H NMR and 13C NMR spectra of the minor product indicate
that it is the 1,3,5-triarolylbenzene derivatives 7 which is assumed to be
formed via intermediacy of 5 and 6. Compounds 7a–e are formed in
good yield on refluxing 1a–e in acetic acid. Trials to add 1c–e to dimethyl
acetylenedicarboxylate failed, only trimerization products 7c–e were
formed. To our knowledge formation of 4 and 7 in their reactions is first
reported high yield synthesis of 1,3,5-trisubstituted benzene derivatives from
enaminones.
Refluxing 1a–b,d in acetic acid in presence of ammonium acetate
afforded the pyridine derivatives 8a–b,d most likely via intermediates 5.
EXPERIMENTAL SECTION
All melting points are uncorrected. IR spectra were recorded in KBr
with a Pye Unicam SP 1100 spectrophotometer. 1H NMR spectra were
recorded on a Varian EM-390 spectrometer in [2H6] DMSOas solvent and
TMS as internal standard; chemical shifts are reported in d units (ppm). Mass
spectra were measured on MS 30 and MS 9 (AEI), 70 eV. Microanalyses
were performed on LECOCHNS-932. Microanalytical data were obtained
from the Microanalytical Data Unit at Cario University.

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ABDEL-KHALIK AND ELNAGDI
General Procedure for the Preparation of 4a–b and 7a–b: A mixture of
each of compound 1a,b (10 mmol) and ethyl propiolate (0.98 g, 10 mmol)
was refluxed in acetic acid (15 ml) for 1 h. The solvent was removed and the
residue cooled to deposit a mixture of the target products. These were
purified by flash chromatography on silica gel using chloroform/n-hexane
(3 :1) as eluent.
Diethyl 5-(2-Furoyl)-1,4-benzencarboxylate (4a): Yield: 2.21Àg1 (70%);
M.p. 155–156ꢀC. – IR (KBr): n ¼ 1721 (C¼Oester), 1640 cm
(C¼O
aroyl). – MS (EI, 70 EV): m/z ¼ 316 (Mþ). – 1H NMR (300 MHz,
DMSO): d ¼ 1.36 (t, 6H, J ¼ 8 Hz, 2CH3), 4.38 (q, 4H, J ¼ 8 Hz, 2 OCH2),
6.80–6.82 (m, 1H, furyl 4-H), 7.52–7.53 (m, 2H, furyl 3-H and 5-H), 8.14 (s,
1H, 2-H), 8.61 (s, 2H, 4-H and 6-H). – 13C{1H} NMR (300 MHz, DMSO):
d ¼ 179.40 (2 CO), 164.20 (CO ester), 151.17 (C-5), 151.12 (furyl C-2),
148.92 (C-6 and C-4), 137.71 (C-1 and C-3), 137.53 (C-2), 132.49 (furyl
C-5), 121.67 (furyl C-3), 112.94 (furyl C-4), 61.51 (2 OCH2), 13.96 (2 CH3).
– C17H16O6 (316.30): calcd. C 64.55, H 5.10; found C 64.32, H 4.93.
Diethyl 5-(2-Thienoyl)-1,4-benzencarboxylate (4a): Yield: 2.39 g (72%);
M.p. 117–118ꢀC. – IR (KBr): n ¼ 1720 (C¼Oester), 1635 cm À1 (C¼Oaroyl).
– MS (EI, 70 EV): m/z ¼ 332 (Mþ). – 1H NMR (300 MHz, DMSO): d ¼ 1.44
(t, 6H, J ¼ 8 Hz, 2CH3), 4.46 (q, 4H, J ¼ 8 Hz, 2 OCH2), 7.28–7.31
(m, 1H, thienyl 4-H), 7.73–7.87 (m, 2H, thienyl 3-H and 5-H), 8.13
(s, 1H, 2-H), 8.52 (s, 2H, 4-H and 6-H). – 13C{1H} NMR (300 MHz,
DMSO): d ¼ 185.55 (CO), 164.18 (CO ester), 138.37 (C-5), 136.34, 132.93,
132.71, 132.08, 131.10, 130.99, 128.87, 61.49 (2 OCH2), 13.97 (2 CH3).
-C17H16O5S (332.30): calcd. C 61.44, H 4.85, S 9.60; found C 61.31,
H 4.84, S 9.66.
General Procedure for the Preparation of 7a–e: Each of compound
1a–e (10 mmol) was refluxed in acetic acid for 2 h, then left to cool at rt.
The target compounds separated as crystals that were collected by filtration
and crystallized from ethanol/dioxane (3 :1 v/v).
1,3,5-(2-Furoyl)benzene (7a): Yield: 3.13 g (87%); M.p. 184–185ꢀC. – IR
(KBr): n ¼ 1650 cmÀ1 (C¼Oaroyl). – MS (EI, 70 EV): m/z ¼ 360 (MÀ).
– 1H NMR (300 MHz, DMSO): d ¼ 6.84–6.85 (m, 3H, furyl 4-H), 7.36–7.44
(m, 3H, furyl 3-H), 7.89–7.94 (m, 3H, furyl 5-H), 8.30 (s, 3H, phenyl
2-H, 4-H, 6-H). – C21H12O6 (360.31): calcd. C 70.00, H 3.36; found C
70.02, H 3.47.
1,3,5-(2-Thienoyl)benzene (7b): Yield: 3.46 g (85%); M.p. 203–204ꢀC.
– IR (KBr): n ¼ 1644 cmÀ1 (C¼Oaroyl). – MS (EI, 70 EV): m/z ¼ 408 (Mþ).
–
1H NMR (300 MHz, DMSO): d ¼ 7.10–7.33 (m, 3H, thienyl 4-H),
7.62–7.95 (m, 3H, thienyl 3-H), 8.18–8.19 (m, 3H, thienyl 5-H), 8.44
(s, 3H, phenyl 2-H, 4-H, 6-H). – C21H12O3S3 (408.31): calcd. C 61.77,
H 2.96, S 23.51; found C 61.73, H 3.01, S 23.65.

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163
1,3,5-(3-Pyridoyl)benzene (7c): Yield: 3.50 g (89%); M.p. 202–204ꢀC.
– IR (KBr): n ¼ 1651 cmÀ1 (C¼Oaroyl). – MS (EI, 70 EV): m/z ¼ 393 (MÀ).
– 1H NMR (300 MHz, DMSO): d ¼ 7.61–7.64 (m, 3H, pyridyl 5-H), 8.24 (d,
3H, J ¼ 8 Hz, pyridyl 4-H), 8.34 (s, 3H, phenyl 2-H, 4-H, 6-H), 8.85 (d, 3H,
J ¼ 8 Hz, pyridyl 6-H), 9.00 (s, 3H, pyridyl 2-H). – C24H15O3N3 (393.38):
calcd. C 73.27, H 3.84, N 10.68; found C 73.00, H 4.07, S 10.56.
1,3,5-Benzoylbenzene (7d): Yield: 3.10 g (79%); M.p. 131–132ꢀC. – IR
(KBr): n ¼ 1659 cmÀ1 (C¼Oaroyl). – MS (EI, 70 EV): m/z ¼ 390 (Mþ).
–
1H NMR (300 MHz, DMSO): d ¼ 7.40–7.73 (m, 9H, benzoyl-H),
7.85–8.06 (m, 6H, benzoyl-H), 8.27 (s, 3H, phenyl 2-H, 4-H, 6-H).
– C27H18O3 (390.41): calcd. C 83.06, H 4.65; found C 82.80, H 4.76.
1,3,5-Acetylbenzene (7e): Yield: 1.32 g (65%); M.p. 154–155ꢀC. – IR
(KBr): n ¼ 1689 cmÀ1 (C¼O). – MS (EI, 70 EV): m/z ¼ 204 (Mþ). – 1H NMR
(300 MHz, DMSO): d ¼ 2.72 (s, 9H, COCH3), 8.71 (s, 3H, phenyl 2-H, 4-H,
6-H). – C18H12O3 (204.22): calcd. C 70.57, H 5.92; found C 70.23, H 6.08.
General Procedure for the Preparation of 8a–b, d: Each of compound
1a–b,d (10 mmol) was refluxed in acetic acid (20 ml) in the presence
of ammonium acetate (1 g) for 2 h, then left to cool at rt. The target
compounds separated as crystals that were collected by filtration and
crystallized from ethanol/dioxane (2 :1 v/v).
2-(Fur-2-yl)-5-(2-furoyl)pyridine (8a): Yield: 2.03 g (85%); M.p. 120–
121ꢀC. – IR (KBr): n ¼ 1643 cmÀ1 (C¼O). – MS (EI, 70 EV): m/z ¼ 239
1
(Mþ). – H NMR (300 MHz, DMSO): d ¼ 6.82–6.83 (m, 1H, furyl 4-H),
6.97–7.02 (m, 1H, furyl 40-H), 7.36 (d, 1H, J ¼ 5 Hz furyl 3-H), 7.54 (d,
1H, J ¼ 5 Hz, furyl 30-H), 7.94 (d, 1H, J ¼ 5 Hz, furyl 5-H), 8.04 (d, 1H,
J ¼ 5 Hz, furyl 50-H), 8.20 (d, 1H, J ¼ 9 Hz, pyridyl 3-H), 8.39 (d, 1H,
J ¼ 9 Hz, pyridyl 4-H), 9.09 (s, 1H, pyridyl 6-H). – C14H9NO3 (239.22):
calcd. C 70.29, H 3.79, N. 5.86; found C 70.32, H 3.66, N 5.89.
2-(Thien-2-yl)-5-(2-thienoyl)pyridine (8b): Yield: 1.95 g (72%); M.p.
115–116ꢀC. – IR (KBr): n ¼ 1640 cmÀ1 (C¼O). – MS (EI, 70 EV):
m/z ¼ 271 (Mþ). – 1H NMR (300 MHz, DMSO): d ¼ 7.29–7.32 (m, 1H,
thienyl 4-H), 7.37–7.40 (m, 1H, thienyl 40-H), 7.84 (d, 1H, J ¼ 5 Hz, thienyl
3-H), 7.93 (d, 1H, J ¼ 5 Hz, thienyl 30-H), 8.06 (d, 1H, J ¼ 5 Hz, thienyl 5-H),
8.17 (d, 1H, J ¼ 9 Hz, pyridyl 3-H), 8.24 (d, 1H, J ¼ 5 Hz, thienyl 50-H), 8.31
(d, 1H, J ¼ 9 Hz, pyridyl 4-H), 9.02 (s, 1H, pyridyl 6-H). – C14H9NOS2
(271.22): calcd. C 61.99, H 3.34, N 5.16, S 23.60; found C 70.12, H 3.26,
N 5.19, S. 23.46.
5-Benzoyl-2-phenylpyridine (8d): Yield: 1.94 g (75%); M.p. 82–83ꢀC.
– IR (KBr): n ¼ 1659 cmÀ1 (C¼O). – MS (EI, 70 EV): m/z ¼ 259 (Mþ).
1
– H NMR (300 MHz, DMSO): d ¼ 7.60–7.91 (m, 8H, arom-H), 8.25–8.28
(m, 4H, arom-H), 9.04 (s, 1H, pyridyl 6-H). – C18H13NO(259.29): calcd. C
83.37, H 5.05, N 5.40; found C 83.50, H 4.81, N 5.54.

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ABDEL-KHALIK AND ELNAGDI
ACKNOWLEDGMENT
We are grateful to Alexander Von Humboldt stiftung for granting a
Stependium to Prof. M. H. Elnagdi. The discussion of Prof. E. Fanghanel at
1
University of Halle is highly appreciated. Some H NMR and 13C NMR
spectra were carried out at University of Halle.
REFERENCES
1. Greenhill, J.V. Advances in Heterocyclic Chemistry 1997, 67, 207–343.
2. Al-Enezi, A.; Al-Saleh, B.; Elnagdi, M.H. J. Chem. Research (S) 1997,
4–5, Ibid (M ), 1997, 116–138.
3. Al-Saleh, B.; Al-Awadi, N.; Al-Kandari, H.; Abdel-Khalik, M.M.;
Elnagdi, M.H. J. Chem. Research (S) 2000, 16–17, Ibid (M ), 2000,
201–214.
4. Al-Omran, F.; Abdel-Khalik, M.M.; Abou El-Khair, A.; Elnagdi, M.H.
Synthesis 1997, 91–94.
5. Al-Zaydi, K.M.; Hafez, E.A.; Elnagdi, M.H. J. Chem. Research (S)
2000, 154, Ibid (M ), 2000, 510, Ibid (M ), 2000, 510–527.
Received in the Netherlands February 28, 2001

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