Three-component reaction of 5,5-dimethylcyclohexan-1,3-dione, aromatic aldehydes, and acetonitrile in the presence of chlorosulfonic acid forming N-[(2-Hydroxy-4,4-dimethyl-6-oxocyclohexene-1-yl)-aryl-methyl]-acetamides

Article abstract of DOI:10.1080/00397910902898643

A three-component reaction between 5,5-dimethylcyclohexan-1,3-dione (dimedone), aromatic aldehydes, and acetonitrile in the presence of chlorosulfonic acid afforded N-[(2-hydroxy-4,4-dimethyl-6-oxocyclohexene-1-yl)- aryl-methyl]-acetamides in good yields.

Full text of DOI:10.1080/00397910902898643

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Three-Component Reaction of
5,5-Dimethylcyclohexan-1,3-
dione, Aromatic Aldehydes,
and Acetonitrile in the
Presence of Chlorosulfonic Acid
Forming N-[(2-Hydroxy-4,4-
dimethyl-6-oxocyclohexene-1-
yl)-aryl-methyl]-acetamides
Mohammad Anary-Abbasinejad a , Alireza
Hassanabadi a & Khadijeh Charkhati a
a Department of Chemistry, Islamic Azad University,
Yazd Branch, Yazd, Iran
Version of record first published: 29 Oct 2009
To cite this article: Mohammad Anary-Abbasinejad, Alireza Hassanabadi & Khadijeh
Charkhati (2009): Three-Component Reaction of 5,5-Dimethylcyclohexan-1,3-dione,
Aromatic Aldehydes, and Acetonitrile in the Presence of Chlorosulfonic Acid Forming
N-[(2-Hydroxy-4,4-dimethyl-6-oxocyclohexene-1-yl)-aryl-methyl]-acetamides,
Synthetic Communications: An International Journal for Rapid Communication of
Synthetic Organic Chemistry, 39:23, 4289-4297
To link to this article: http://dx.doi.org/10.1080/00397910902898643

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Synthetic Communications1, 39: 4289–4297, 2009
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910902898643
Three-Component Reaction of
5,5-Dimethylcyclohexan-1,3-dione, Aromatic
Aldehydes, and Acetonitrile in the Presence of
Chlorosulfonic Acid Forming
N-[(2-Hydroxy-4,4-dimethyl-6-oxocyclohexene-
1-yl)-aryl-methyl]-acetamides
Mohammad Anary-Abbasinejad, Alireza Hassanabadi, and
Khadijeh Charkhati
Department of Chemistry, Islamic Azad University,
Yazd Branch, Yazd, Iran
Abstract: A three-component reaction between 5,5-dimethylcyclohexan-1,3-dione
(dimedone), aromatic aldehydes, and acetonitrile in the presence of chlorosulfonic
acid afforded N-[(2-hydroxy-4,4-dimethyl-6-oxocyclohexene-1-yl)-aryl-methyl]-
1
acetamides in good yields. The temperature-dependent H NMR of one of the
products has been investigated.
Keywords: Aromatic aldehydes, chlorosulfonic acid, 5,5-dimethylcyclohexan-1,
1
3-dione, multicomponent reaction, temperature-dependent H NMR
Multicomponent reactions (MCRs) have attracted considerable interest
from organic chemists because they can be widely employed for the rapid
assembly of arrays with high molecular diversity.[1] These processes are
performed without need to isolate any intermediate, and this reduces time
and saves both energy and raw materials.[2,3]
Received January 29, 2009.
Address correspondence to Mohammad Anary-Abbasinejad, Department
of Chemistry, Islamic Azad University, Yazd Branch, P. O. Box 89195-155, Yazd,
Iran. E-mail: mohammadanary@yahoo.com
4289

4290
M. Anary-Abbasinejad, A. Hassanabadi, and K. Charkhati
Acetamido- or amino-ketone derivatives are important for their
biological and pharmaceutical properties[4,5] and in the preparation of
antibiotic drugs such as nikkomycine or neopolyoxines.[6,7]
A three-component reaction of acetophenone derivatives, as enolic
systems, aromatic aldehydes, and acetonitrile has been used for the synth-
esis of b-acetamidoketones.[8] This reaction usually has been carried out in
the presence of an excess amount of acetyl chloride and catalyzed by dif-
ferent Brønsted or Lewis acids. A similar catalytic reaction has been
reported with other enolic compounds such as 2-naphthol, aromatic alde-
hydes, and acetonitrile.[9] Recently, we reported the reaction of 2-naphthol
derivatives or 4-hydroxycoumarin with aromatic aldehydes and acetoni-
trile promoted by chlorosulfonic acid, affording acetamidoalkylnaphthol
or acetamidoalkylcoumarin derivatives, respectively.[10,11] We also
reported a pseudo-three-component reaction between electron-deficient
aromatic aldehydes and acetonitrile in the presence of chlorosulfonic
acid, producing symmetrical N,N0-bisamide derivatives.[12] Here, we
report the three-component reaction of 5,5-dimethylcyclohexan-1,3-dione
(dimedone), aromatic aldehydes, and acetonitrile in the presence of chlor-
osulfonic acid forming N-[(2-hydroxy-4,4-dimethyl-6-oxocyclohexene-
1-yl)-aryl-methyl]-acetamides in good yields (Scheme 1). Thus, treatment
of dimedone (1) and 2-methoxybenzaldehyde (2a) in boiling acetonitrile
in the presence of 2 eq chlorosulfonic acid after workup afforded
Scheme 1. Three-component reaction of dimedon, aromatic aldehydes, and
acetonitrile.

Reaction of Dimedone, Aldehydes, and Acetonitrile
4291
N-[(2-hydroxy-4,4-dimethyl-6-oxocyclohexene-1-yl)-(2-methoxyphenyl)-
methyl]-acetamide 3a in 90% yield.
The mass spectrum of compound 3a showed the molecular ion peak
at 317, which is consistent with the proposed structure. The infrared (IR)
spectrum of 3a exhibited a sharp absorption band at 3430 cmꢀ1 for NH
band and a broad strong group at 1653 cmꢀ1 for carbonyl groups. The 1H
NMR spectrum of compound 3a showed a single signal at 12.11 ppm for
the OH proton, which disappeared by addition of D2O. The NH and
methine protons coupled to each other, and two double signals
(3JHH ¼ 6 HZ) were observed for them at 8.21 and 6.43 ppm, respectively.
After addition of D2O, the signal related to the NH proton disappeared,
and the signal related to the methine proton converted to a singlet. The
aromatic protons showed characteristic signals between 6.79 and
7.20 ppm. Two sharp signals were observed at 3.66 and 1.85 ppm for
methoxy and acetyl group protons, and a 6-H singlet observed at
0.93 ppm was attributed to the protons of two methyl groups of dimedon
moiety. A very broad signal was observed at 2.28 ppm for the protons of
two methylene groups. Considering the proposed structure for compound
3a, it seems that two methylene groups of dimedone moiety are heteroto-
1
pic, and two signals are expected for them in the H NMR spectrum of
3a. However, if this structure is in equilibrium with its degenerate tauto-
mer (Scheme 2), and the rate of the interconversion of two tautomers is
1
high, then the H NMR will show one average signal for the protons of
two methylene groups. The protons of each methylene group are diaster-
eotopic, and if the interconversion rate is slow, two AB-quartet signals
are expected for two methylene groups. To investigate the effect of the
interconversion rate between 3a and 3a0, we recorded the 1H NMR spec-
trum of compound 3a in different temperatures, and the results are
1
shown in Figs. 1 and 2. As shown in Fig. 1, in the H NMR spectrum
of 3a at low temperatures, protons of one of the methylene groups
appeared as an AB-quartet at 2.51 ppm, and the protons of the other
Scheme 2. Tautomerization of compound 3a.

4292
M. Anary-Abbasinejad, A. Hassanabadi, and K. Charkhati
Figure 1.
one appeared as a multiplet at 2.27 ppm. Figure 2 shows the changes in
the chemical shifts of aromatic, NH, and methine protons with tempera-
ture. Among the aromatic protons, the largest change in the chemical
shift was observed for the C-6 proton, which is the closest one to the
Figure 2.

Reaction of Dimedone, Aldehydes, and Acetonitrile
4293
Scheme 3. Suggested mechanism for formation of compounds 3a–e.
dimedone moiety. The 13C NMR spectrum of compound 3a exhibited 14
signals, in agreement with the proposed structure. A broad signal was
observed at 45.5 ppm for two methylene carbons and a signal appeared
at 179.4 ppm for C-2 and C-6 carbons of dimedone moiety. The signals
related to these two carbons are coincided as the result of fast introver-
sion of two tautomers of compound 3a.
To study the scope of the reaction, different aldehydes were treated
with dimedone at boiling acetonitrile in the presence of chlorosulfonic
acid. As shown in Scheme 1, the reaction was compatible with aldehydes
substituted by electron-releasing groups such as 2- and 4-methoxybenzal-
dehyde or weakly electron-attracting groups such as 4-chloro and 4-
bromobenzaldehyde. When strongly electron-deficient aldehydes such
as 3- and 4-nitrobenzaldehyde were used, no product was isolated. When
2-nitrobenzaldehyde was used, however, the desired product was
obtained in 33% yield. We also examined the similar reaction of aromatic
aldehydes with other 1,3-dicarbonyl compounds such as indan-1,3-dione
or N,N0-dimethylbarbituric acid in acetonitrile in the presence of chloro-
sulfonic acid, but the desired products were not obtained.
A suggested mechanism for formation of compounds 3a-e is shown
in Scheme 2. The Knovenagel condensation of aldehyde with dimedone
in the presence of chlorosulfonic acid afforded enone 4, which underwent
a Michael addition by acetonitrile promoted by chlorosulfonic acid to
produce nitrilium cation 5 that hydrolyzes during the workup of the
reaction to product 3.

4294
M. Anary-Abbasinejad, A. Hassanabadi, and K. Charkhati
In summary, we report herein the reaction of aromatic aldehydes,
dimedone, and acetonitrile in the presence of chlorosulfonic acid, which
provided a simple method for the synthesis of N-[(2-hydroxy-4,4-
dimethyl-6-oxocyclohexene-1-yl)-aryl-methyl]-acetamides in good yields.
EXPERIMENTAL
Melting points were determined with an electrothermal 9100 apparatus
and are uncorrected. Elemental analyses were performed at the
Analytical Laboratory of Islamic Azad University, Yazd Branch, using
a Costech ECS 4010 CHNS-O analyzer. Mass spectra were recorded
on a Finnigan-MAT 8430 mass spectrometer operating at an ionization
potential of 70 eV. IR spectra were recorded on a Shimadzu IR-470 spec-
1
trometer. H and 13C NMR spectra were recorded on Bruker DRX-500
1
Avance spectrometer at 500.1 and 125.8 MHz, respectively. H and 13C
NMR spectra were obtained on solution in d6-DMSO using tetramethyl-
silane (TMS) as internal standard. The chemicals used in this work were
purchased from Fluka (Buchs, Switzerland) and were used without
further purification.
General Procedure
A solution of aldehyde (2 mmol), dimedone (2 mmol), and chlorosulfonic
acid (4 mmol) in 15 mL acetonitrile was refluxed for 3 h. The reaction
mixture was then poured into ice water (50 mL). The precipitate was
filtered and crystallized from an ethyl acetate–hexane mixture.
N-[(2-Hydroxy-4,4-dimethyl-6-oxocyclohexene-1-yl)-(2-methoxyphenyl)-
methyl]-acetamide (3a)
White powder; mp 137–139ꢁC. IR (KBr) (nmax, cmꢀ1): 3430 (NH), 1653
þ.
=
(C O). MS, m=z (%): 317 (M , 9), 274 (23), 217 (75), 227 (53), 146 (27),
43 (100). Anal. calcd. for C18H23NO4: C, 68.12; H, 7.30; N, 4.41%.
1
Found: C, 68.3; H, 7.5; N, 4.3%. H NMR (500 MHz, d6-DMSO): d
0.93 (6 H, s, 2 CH3), 1.85 (3 H, s, CH3), 2.28 (4 H, s, 2 CH2), 3.66 (3 H,
s, OCH3), 6.43 (1 H, d, 3JHH ¼ 6 Hz, CH), 6.75 (1 H, d, 3JHH ¼ 7 Hz, aro-
3
3
matic), 6.83 (1 H, t, JHH ¼ 7 Hz, aromatic), 7.11 (1 H, t, JHH ¼ 7 Hz,
aromatic), 7.28 (1 H, d, 3JHH ¼ 7 Hz, aromatic), 8.21 (1 H, d, 3JHH ¼ 6 Hz,
NH), 12.11 (1 H, broad s, OH). 13C NMR (125.8 MHz, d6-DMSO): d

Reaction of Dimedone, Aldehydes, and Acetonitrile
4295
23.6 (2 CH3), 28.9 (CH3), 33.3 (C), 43.1 (CH), 45.5 (2 CH2), 56.0 (OCH3),
=
111.2 (C CꢀOH), 114.3, 120.2, 127.9, 128.6, 131.3 and 157.2 (aromatic),
=
=
169.3 (C O amide), 184.4 (C CꢀOH).
N-[(2-Hydroxy-4,4-dimethyl-6-oxocyclohexene-1-yl)-(4-methoxyphenyl)-
methyl]-acetamide (3b)
White powder; mp 165–167ꢁC. IR (KBr) (nmax, cmꢀ1): 3430 (NH), 1610
þ.
=
(C O). MS, m=z (%): 317 (M , 7), 274 (27), 217 (53), 227 (37), 117 (44),
43 (100). Anal. calcd. for C18H23NO4: C, 68.12; H, 7.30; N, 4.41%.
1
Found: C, 68.2; H, 7.5; N, 4.6%. H NMR (500.1 MHz, d6-DMSO): d
0.96 (6 H, s, 2 CH3), 1.89 (3 H, s, CH3), 2.28 (4 H, s, 2 CH2), 3.68 (3 H,
s, OCH3), 6.21 (1 H, d, 3JHH ¼ 6 Hz, CH), 6.95 (2 H, d, 3JHH ¼ 8 Hz, aro-
3
3
matic), 7.83 (2 H, d, JHH ¼ 8 Hz, aromatic), 8.42 (1 H, d, JHH ¼ 6 Hz,
NH), 11.21 (1 H, broad s, OH). 13C NMR (125.8 MHz, d6-DMSO): d
23.8 (2 CH3), 28.7 (CH3), 32.6 (C), 45.2 (CH), 46.1 (2 CH2), 55.8
=
(OCH3), 114.0 (C CꢀOH), 127.8, 129.5, 135.8 and 158.3 (aromatic),
=
=
169.1 (C O amide), 185.9 (C CꢀOH).
N-[(2-Hydroxy-4,4-dimethyl-6-oxocyclohexene-1-yl)-(4-bromophenyl)-
methyl]-acetamide (3c)
White powder; mp 203–207ꢁC. IR (KBr) (nmax, cmꢀ1): 3375 (NH), 1609
þ
=
(C O). MS, m=z (%): 365 (M , 3), 322 (38), 305 (49), 226 (63), 139 (11),
43 (100). Anal. calcd. for C17H20BrNO3: C, 55.75; H, 5.50; N, 3.82%.
1
Found: C, 55.9; H, 5.4; N, 3.7%. H NMR (500 MHz, d6-DMSO): d
0.91 (6 H, s, 2 CH3), 1.82 (3 H, s, CH3), 2.32 (4 H, s, 2 CH2), 6.21 (1 H,
3
3
d, JHH ¼ 6 Hz, CH), 7.11 (2 H, d, JHH ¼ 8 Hz, aromatic), and 7.41
3
3
(2 H, d, JHH ¼ 8 Hz, aromatic), 8.03 (1 H, d, JHH ¼ 6 Hz, NH), 11.79
(1 H, broad s, OH). 13C NMR (125.8 MHz, d6-DMSO): d 23.9 (2 CH3),
=
27.9 (CH3), 31.8 (C), 42.2 (CH), 45.3 (2 CH2), 114.3 (C CꢀOH),
=
119.6, 129.8, 131.4 and 143.9 (aromatic), 169.4 (C O amide), 183.8
=
(C CꢀOH).
N-[(2-Hydroxy-4,4-dimethyl-6-oxocyclohexene-1-yl)-(4-chlorophenyl)-
methyl]-acetamide (3d)
White powder; mp 143–145ꢁC. IR (KBr) (nmax, cmꢀ1): 3195 (NH), 1653
þ
=
(C O). MS, m=z (%): 321 (M , 7), 278 (38), 261 (43), 226 (50), 139 (7), 43
(100). Anal. calcd. for C17H20ClNO3: C, 63.45; H, 6.26; N, 4.35%.

4296
M. Anary-Abbasinejad, A. Hassanabadi, and K. Charkhati
Found: C, 63.2; H, 6.1; N, 4.5%. 1H NMR (500 MHz, d6-DMSO): d 0.98
(6 H, s, 2 CH3), 1.84 (3 H, s, CH3), 2.46 (4 H, s, 2 CH2), 6.75 (1 H, d,
3
3JHH ¼ 6 Hz, CH), 7.14 (2 H, d, JHH ¼ 8 Hz, aromatic), and 7. 46 (2 H,
3
3
d, JHH ¼ 8 Hz, aromatic), 8.57 (1 H, d, JHH ¼ 6 Hz, NH), 12.11 (1 H,
broad s, OH). 13C NMR (125.8 MHz, d6-DMSO): d 23.9 (2 CH3), 27.9
=
(CH3), 31.8 (C), 42.2 (CH), 45.1 (2 CH2), 111.8 (C CꢀOH), 119.1,
=
129.3, 131.6 and 143.2 (aromatic), 169.5 (C O amide), 180.1
=
(C CꢀOH).
N-[(2-Hydroxy-4,4-dimethyl-6-oxocyclohexene-1-yl)-(2-nitrophenyl)-
methyl]-acetamide (3e)
White powder; mp 182–184ꢁC. IþR (KBr) (nmax, cmꢀ1): 3209 (NH), 1659
=
(C O). MS, m=z (%): 332 (M , 5), 289 (77), 272 (43), 139 (17), 43
(100). Anal. calcd. for C17H20N2O5: C, 61.44; H, 6.07; N, 8.43%. Found:
C, 61.6; H, 5.9; N, 8.5%. 1H NMR (500 MHz, d6-DMSO): d 0.92 (6 H, s, 2
3
CH3), 1.88 (3 H, s, CH3), 2.12 (4 H, s, 2 CH2), 6.54 (1 H, d, JHH ¼ 6 Hz,
3
3
CH), 7.32 (1 H, d, JH H ¼ 7 Hz, aromatic), 7.38 (1 H, t, JHH ¼ 7 Hz,
aromatic), 7.53 (1 H, t,3JHH ¼ 7 Hz, aromatic), 7.64 (1 H, d, JHH ¼ 7 Hz,
3
aromatic), 8.04 (1 H, d, JHH ¼ 6 Hz, NH), 11.9 (1 H, broad s, OH). 13C
3
NMR (125.8 MHz, d6-DMSO): d 21.8 (2 CH3), 27.3 (CH3), 30.5 (C),
=
42.6 (CH), 45.9 (2 CH2), 111.5 (C CꢀOH), 122.8, 123.7, 127.8, 132.5,
=
=
136.4 and 147.7 (aromatic), 168.1 (C O amide), 186.1 (C CꢀOH).
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