Expeditious synthesis of aromatic cyanodienones using neutral alumina as a versatile heterogeneous catalyst

Article abstract of DOI:10.1080/00397911.2013.831103

The work described herein employs neutral alumina as an effective catalyst for ring opening of triarylpyrylium perchlorates to corresponding aromatic cyanodienones, which have main roles in biological activities. The present porous catalyst has several ad

Full text of DOI:10.1080/00397911.2013.831103

Synthetic Communications1, 44: 640–647, 2014
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2013.831103
EXPEDITIOUS SYNTHESIS OF AROMATIC
CYANODIENONES USING NEUTRAL ALUMINA
AS A VERSATILE HETEROGENEOUS CATALYST
Arash Mouradzadegun and Fatemeh Abadast
Department of Chemistry, Faculty of Science, Shahid Chamran University,
Ahvaz, Iran
GRAPHICAL ABSTRACT
Abstract The work described herein employs neutral alumina as an effective catalyst for
ring opening of triarylpyrylium perchlorates to corresponding aromatic cyanodienones,
which have main roles in biological activities. The present porous catalyst has several advan-
tages, it is inexpensive, thermally and mechanically stable, nontoxic, and highly resistant
against organic solvents. It increases the reaction rate many fold when compared with
conventional reaction conditions. Moreover, the recovered alumina can be used several
times without serious decrease in activity.
[Supplementary materials are available for this article. Go to the publisher’s online
edition of Synthetic Communications1 for the following free supplemental resource(s):
Full experimental and spectral details.]
Keywords Aromatic cyanodienone; heterogeneous catalysis; neutral alumina; pyrylium
salt
INTRODUCTION
Transition aluminas are some of the most widely used materials in
heterogeneous catalysis because of several attractive features.[1] They are applied
industrially as filler, absorbent, drying agent, catalyst, catalyst support, and reagent
in a wide variety of chemical processes.[2] Among the transition aluminas, c-alumina
Received June 15, 2013.
Address correspondence to Arash Mouradzadegun, Department of Chemistry, Faculty of Science,
Shahid Chamran University, Ahvaz, Iran. E-mail: arash_m@scu.ac.ir
640

SYNTHESIS OF CYANODIENONES
641
plays a pivotal role in the industry, with numerous applications in refining and
petrochemistry.[3] Further theoretical and experimental investigations revealed that
neutral alumina, unlike clays and zeolites, does not contain accessible channels or
cavities; however, it shows large surface area and highly porous exteriors available
to substrates. It could be most commonly utilized as a catalyst as a support for
the effective synthesis of target molecules.[4]
Cyanodienone derivatives, especially aromatic ones, have found use as elegant
precursors to produce potent antibiotics such as butenolides,[5] which appear as a
substructure in natural products, peptide analogs, and HIV-1 protease inhibitors.[6]
One of the major drawbacks for the synthesis of these biologically important mole-
cules starting from readily available triarylpyrylium perchlorates is much longer
reaction time (e.g., 23 h for 1F). Although our preceding effort in the green synthesis
of these compounds using cyanide impregnated on anion exchange resin[7] decreased
the reaction time to some extent, it is still a great challenge to construct these
molecules using a simple cost-effective method that can be amenable to large-scale
production and provide a significant tool with important implications in pharmaco-
logical industries.
In continuation to our studies on developing improved synthetic methodolo-
gies for organic transformation,[8] in the present paper, we describe a highly efficien-
tand convenient approach toward the synthesis of aromatic cyanodienones by
reaction of corresponding triarylpyrylium perchlorates with sodium cyanide using
c-alumina as common, cheap, and neutral heterogeneous catalyst.
RESULTS AND DISCUSSION
The performance of aluminas, in general, as catalyst or catalyst supports
largely depends on their crystalline, textural, and chemical characteristics, as well
as on their hydrothermal stabilities.[9] Empirical testing of several supports revealed
that neutral alumina was most effective in activating cyanide.[10] Previous studies
clearly showed that neutral alumina impregnated with cyanide (NaCN=c-A12O3)
is a more efficient reagent for carrying out cyanide displacement on organic halides.
The reagent affords excellent yields of the desired products but the reaction proceeds
relatively slow. This was described by the fact that NaCN=c-A12O3 is uniformly dis-
tributed between active and inactive sites and that only monolayer coverage is of
practical synthetic value. Moreover, the inactive cyanide was tentatively attributed
to material located in small pores, inaccessible to the bulk organic phase.[11] So, to
put the reactivity of impregnated cyanide ion into perspective, we have arranged
the competitive and parallel analogous conversion reactions of triphenylpyrylium
perchlorate as a model compound in the presence of pulverized NaCN and CNꢀ=
c-A12O3 as reagents (Scheme 1).
First, the reaction of triarylpyrylium perchlorate with sodium cyanide was
chosen as the model reaction to survey the requisite reaction condition. To know
the solvent effect on the outcome of the reaction, different solvents were screened
in the model reaction. It was observed that acetonitrile was the most effective sol-
vent, furnishing the desired product in 78% yield superior to ethanol, dichloro-
methane, and tetrahydrofuran. Turning our attention to the molar ratio of
reagent=substrate, the reaction of model compound (1 mmol) with varying amount

642
A. MOURADZADEGUN AND F. ABADAST
Scheme 1. Synthesis of aromatic cyanodienones 2 from the reaction of triarylpyrylium perchlorates 1 with
NaCN and CNꢀ=c-Al2O3.
Table 1. Trend of the model reaction with different amounts of sodium cyanide
Entry
Reagent=substrate
Time
Yield of 2 (%)
1
2
3
4
1
1 h
78
78
78
65
1.5
2
50 min
30 min
15 min
2.5
of sodium cyanide was investigated. As can be observed in Table 1, the target reac-
tion is favored by increasing the reagent=substrate ratio as shown from the signifi-
cant decrease in the reaction time. Bearing in mind that the reaction proceeds
through an addition and then ring-opening mechanism, the increase in reagent con-
centration favors the first reaction step and, on the whole, the product formation.
The decrease of the yield (65%) by employing a ratio of 2.5 (entry 4) can probably
be explained by generation of other products. The best yield (78%) and the shortest
time (30 min) were obtained by using the ratio reagent of substrate ¼ 2 (entry 3). This
molar ratio was considered in both cases of reagents.
Neutral alumina impregnated with cyanide was allowed to react with the model
compound. Unlike other experiments,[10,11] the reaction was performed at high
speed. This extraordinary result supported the assumption that perhaps besides
the role of the surface area, the pore structure plays an important role in alumina
activity. Therefore, we have arranged the reaction of model compound with sodium
cyanide in the presence of a catalytic amount of c-A12O3. The reaction was successful
and cyanodienone 2A was obtained quickly with good yield. Encouraged by this
Table 2. Trend of the model reaction with different amounts of catalyst
Entry
Catalyst (mol%)
Time (min)
1
2
3
3
5
5
3
3
10

SYNTHESIS OF CYANODIENONES
643
Table 3. Conversion of various triarylpyrylium salts 1 into corresponding aromatic cyanodienones 2 in
acetonitrile at room temperature
Time
(without
Time
(with
catalyst) catalyst) Yield%
Entry
A
Substrate (1)
Product (2)
30 min
3 min
5 min
78
81
B
C
D
E
F
1 h
4 h
15 min
18 min
22 min
30 min
91
95
93
88
10 h
16 h
23 h
G
H
25 min
20 min
2 min
1 min
70
72

644
A. MOURADZADEGUN AND F. ABADAST
observation, further experiments were designed to survey catalytic virtue of
the support in the same reaction. In this regard, the model reaction was
investigated in the presence of various amounts of c-A12O3 as catalyst. As shown
in Table 2, the use of as little as 3 mol% of c-A12O3 is sufficient to catalyze the reac-
tion (entry 1).
˚
We believed that considering the average pore diameter of c-A12O3 [40 A
˚
˚
(20% being >120 A)] and the size of triphenylpyrylium perchlorate [9.5 ꢁ 12 A],
highly porous neutral alumina could constrain substrate or parts of it along
with reactant, lower the entropy of activation of reaction, and accelerate the
reaction.
To further examine the efficacy of this synthetic opportunity, the process is
illustrated with various triarylpyrylium perchlorates contain electron-donating and
withdrawing groups in the para position of substituted phenyl rings with pulverized
sodium cyanide in the presence of neutral alumina (Table 3).
The data in Table 3 clearly showed that reactions of triarylpyrylium salts
with sodium cyanide proceed slowly, while the presence of neutral alumina, in
nearly all cases, incredibly increased the rate of reactions. The effect of substitu-
tions was also viewed clearly in this table. The electron-donating groups cause the
reactions to become slow (e.g., entries A–F). This may be explained by consider-
ing the fact that these groups decrease the positive charge on a-position of the
heterocyclic ring. Stronger electron-donating groups exhibit longer reaction times.
In contrast, electron-withdrawing groups (e.g., entries G and H) accelerate the
reaction.
The structure of all products were settled from their physical and spectroscopic
1
(IR, H NMR, 13C NMR) data.
Furthermore, we regard the recoverability of the c-A12O3 in accordance
with the heterogeneity of this system. The recovered catalyst (after washing with
acetonitrile) was used in the next run with nearly consistent activity.
In summary, the superiority of using c-A12O3 over other methods includes a
very rapid reaction with readily available catalyst. Further, our method can be
applied to a wide range of substrates and results in good yield. Overall, the present
protocol offers more efficient and particularly economically advantageous process
towards the synthesis of valuable aromatic cyanodienones, which serves a useful
synthetic alternative for large-scale conversions. Studies on the applications of this
intriguing and cost-cutting approach in organic transformations are currently under
way in our laboratory.
EXPERIMENTAL
Chemicals were purchased from Fluka, Merck, and Aldrich chemical compa-
nies. Monitoring of the reactions was accomplished by thin-layer chromatography
(TLC). Infrared (IR) spectra were obtained on a Bomen MB:102 FT-IR spectro-
photometer. 1H NMR and 13C NMR spectra were recorded on a Brucker
spectrometer at 400 and 100 MHz, respectively, in CDCl3 with tetramethylsilane
as an internal standard. Mass spectra (MS) were measured on Anagilent 5975 mass
spectrophotometer.

SYNTHESIS OF CYANODIENONES
645
General Procedure for the Synthesis of Triarylpyrylium Perchlorates
All triarylpyrylium perchlorates were synthesized from the corresponding alde-
hydes and ketones by the method previously described.[12] Briefly, corresponding
benzaldehyde (0.1 mol) and acetophenone (0.2 mol) were stirred at room tempera-
ture, and sulfuric acid (6 mL) was added dropwise during 30 min. The mixture was
stirred at 100 ꢂC for 60 min. Then, ethanol (200 mL) and perchloric acid 70%
(10 mL) were added. The mixture was excluded to form a precipitate for 24 h. The
precipitates recrystallized from acetic acid.
General Procedure for the Reaction of Triarylpyrylium Perchlorates
with Sodium Cyanide
The triarylpyrylium perchlorates (1 mmol) were stirred with sodium cyanide
(2 mmol) at room temperature in acetonitrile (10 mL), and the reactions were mon-
itored by TLC using a 20:80 mixture of ether–n-hexane as eluent. After completion
of the reaction, the solvent was evaporated under vacuum and the product 2 was
worked up in aqueous ethyl acetate (to remove excess cyanide), then recrystallized
from EtOH.
General Procedure for the Reaction of Triarylpyrylium Perchlorates
with Cyanide Impregnated on Neutral Alumina
A 50-ml round-bottom flask was charged with 2.0 g (40.8 mmol) of sodium
cyanide dissolved in 5 ml of distilled water, and then 8.0 g of c-alumina was added.
The flask was transferred to a rotary evaporator, and the water was removed under
reduced pressure, keeping the bath temperature below 65 ꢂC. Impregnated alumina
was then dried (4 h, 110 ꢂC). Then, in a round-bottomed flask, a solution of triaryl-
pyrylium perchlorate (1 mmol) in acetonitrile (10 mL) was prepared. Cyanide
impregnated on c-alumina (2 mmol) was added and the mixture was stirred at room
temperature for the appropriate time. The progress of the reaction was monitored by
TLC (eluent: ether–n-hexane 1:4). After completion of the reaction, alumina
removed by filtering, the solvent was evaporated under vacuum, and product 2
was worked up in aqueous ethyl acetate. Then the products were recrystallized from
EtOH.
General Procedure for the Reaction of Triarylpyrylium Perchlorates
with Sodium Cyanide in the Presence of Neutral Alumina as Catalyst
Neutral alumina (0.05 mmol) was added to a magnetically stirred mixture
of the triarylpyrylium salts (1 mmol) and sodium cyanide (2 mmol) in acetoni-
trile (10 mL). The resulting mixture was stirred at room temperature for the
appropriate time. After completion of the reaction, alumina was removed by fil-
tering, the solvent was evaporated under vacuum, and the product 2 was
worked up in aqueous ethyl acetate. Then the products were recrystallized from
EtOH.

646
A. MOURADZADEGUN AND F. ABADAST
SUPPORTING INFORMATION
1
Full experimental detail and H and 13C NMR spectra can be found via the
Supplementary Content section of this article’s Web page.
ACKNOWLEDGMENT
This work was supported by the Research Council at the University of Shahid
Chamran.
REFERENCES
1. Marquez-Alvarez, C.; Zilkova, N.; Perez-Pariente, J.; Cejka, J. Catal. Rev.-Sci. Eng. 2008,
50, 222–286.
2. (a) Baumann, T. F.; Gash, A. E.; Chin, S. C.; Sawvel, A. M.; Maxwell, R. S.; Satcher Jr.,
J. H. Chem. Mat. 2005, 17, 395–401; (b) Shaterian, H. R.; Hosseinian, A.; Ghashang, M.
Synth. Commun. 2008, 38, 4097–4106; (c) Kosydar, R.; Drelinkiewicz, A.; Lalik, E.;
Gurgul, J. Appl. Catal. A: Gen. 2011, 402, 121–131; (d) Gandarias, I.; Requies, J.; Arias,
P. L.; Armbruster, U.; Martin, A. J. Catal. 2012, 290, 79–89; (e) Zhang, Z.; Hicks, R. W.;
Pauly, T. R.; Pinnavaia, T. J. J. Am. Chem. Soc. 2002, 124, 1592–1593; (f) Tumma, H.;
Nagaraju, N.; Reddy, K. V. Synth. Commun. 2010, 40, 1856–1866; (g) Avramescu, S.
M.; Bradu, C.; Udrea, I.; Mihalache, N.; Ruta, F. Catal. Commun. 2008, 9, 2386–2391;
(h) Leita, B. A.; Grayb, P.; O’Sheab, M.; Burkea, N.; Chianga, K.; Trimma, D. Catal.
Today 2011, 178, 98–102.
3. (a) Cai, S.-H.; Rashkeev, S. N.; Pantelides, S. T.; Sohlberg, K. Phys. Rev. B 2003, 67,
1–10; (b) Krokidis, X.; Raybaud, P.; Gobichon, A.-E.; Rebours, B.; Euzen, P.; Toulhoat,
ˇ
H. J. Phys. Chem. B 2001, 105, 5121–5130; (c) Marquez-Alvarez, C.; Zilkova, N.; Perez-
´ ´ ´
ˇ
Pariente, J.; Cejka, J. Catal. Rev. 2008, 50, 222–286; (d) Kagyrmanova, A. P.;
Chumachenko, V. A.; Korotkikh, V. N.; Kashkin, V. N.; Noskov, A. S. Chem. Eng. J.
2011, 176, 188–194.
4. (a) Ballini, R.; Bosico, G.; Fiorini, D.; Palmieri, A. Green Chem. 2005, 7, 825–827; (b)
Jain, S. L.; Prasad, V. V. D. N.; Sain, B. Catal. Commun. 2008, 9, 499–503; (c)
Abdollahi-Alibeik, M.; Mohammadpoor-Baltork, I.; Zolfigol, M. A. Bioorg. Med. Chem.
Lett. 2004, 14, 6079–6082; (d) Hirano, M.; Yakabe, S.; Monobe, H.; Morimoto, T.
J. Chem. Res., Synop. 1998, 472–473; (e) Chriman, W.; Blankinship, M. J.; Taylor, B.;
Harris, C. E. Tetrahedron Lett. 2001, 42, 4775–4777.
5. Balaban, A. T.; Tudose, A.; Caproiu, M. T. Tetrahedron. 2003, 59, 3291–3295.
6. (a) Harris, L. J.; Alexander, N. J.; Saparno, A.; Blackwell, B.; McCormick, S. P.;
´
Desjardins, A. E.; Robert, L. S.; Tinker, N.; Hattori, J.; Piche, C.; Schernthaner, J. P.;
Watson, R.; Ouellet, T. Fungal Genet. Biol. 2007, 44, 293–306; (b) Zhang, X.; Guo, J.;
Hu, S. Synth. Commun. 2012, 42, 1551–1558; (c) Karade, N. N.; Gampawar, S. V.;
Kondre, J. M.; Shinde, S. V. Tetrahedron Lett. 2008, 49, 4402–4404; (d) Sabitha, G.;
Prasad, M. N.; Ramesh, M.; Yadav, J. S. Monatsh. Chem. 2010, 141, 1245–1248; (e)
Fan, W. Y.; Wang, Z. L.; Zhang, Z. G.; Li, H. C.; Deng, W. P. Tetrahedron. 2011, 67,
5596–5603; (f) Clark, B.; Capon, R. J.; Lacey, E.; Tennant, S.; Gill, J. H.; Bulheller, B.;
Bringmann, G. J. Nat. Prod. 2005, 68, 1226–1230; (g) Wu, J.; Zhu, Q.; Wang, L.; Fathi,
R.; Yang, Z. J.Org. Chem. 2003, 68, 670–673; (h) Du, G.-F.; He, L.; Gu, C.-Z.; Dai, B.
Synth. Commun. 2012, 42, 1226–1233.
7. Mouradzadegun, A.; Abadast, F. Monatsh. Chem. 2013, 144, 375–379.

SYNTHESIS OF CYANODIENONES
647
8. (a) Mouradzadegun, A.; Gheitasvand, N. Phosphorus, Sulfur Silicon Relat. Elem. 2005,
180, 1385–1388; (b) Ganjali, M. R.; Norouzi, P.; Emami, M.; Golmohamadi, M.; Pirelahi,
H.; Mouradzadegun, A. J. Chin. Chem. Soc. 2006, 53, 1209–1214; (c) Mouradzadegun, A.;
Pirelahi, H. J. Photochem. Photobiol. A: Chem. 2001, 138, 203–205; (d) Mouradzadegun,
A.; Dianat, Sh. J. Heterocycl. Chem. 2009, 46, 778–781; (e) Mouradzadegun, A.; Ghasem
Hezave, F.; Karimnia, M. Phosphorus, Sulfur Silicon Relat. Elem. 2010, 185, 84–87;
(f) Kiasat, A. R.; Mouradzadegun, A.; Elahi, S.; Fallah-Mehrjardi, M. Chin. Chem. Lett.
2010, 21, 146–150; (g) Mouradzadegun, A.; Kiasat, A. R.; KazemianFard, P. Catal.
Commun. 2012, 29, 1–5; (h) Mouradzadegun, A.; Abadast, F. Tetrahedron Lett. 2013,
54, 2641–2644.
9. Sun, Z.-X.; Zheng, T.-T.; Bo, Q.-B.; Du, M.; Forsling, W. J. Colloid Interface Sci. 2008,
319, 247–251.
10. Regen, S. L.; Quici, S.; Liaw, S. J. J. Org. Chem. 1979, 44, 2029–2030.
11. Regen, S. L.; Quici, S.; Ryan, M. D. J. Am. Chem. Soc. 1979, 101, 7629–7630.
12. (a) Balaban, A. T.; Dinculescu, A.; Dorofeenko, G. N.; Fischer, G. W.; Koblik, A. V.;
Mezheritskii, V. V.; Schroth, W. Advances in Heterocyclic Chemistry; A. R. Katritzky
(Ed.); Academic: New York, 1982, vol. 2, suppl 1; (b) Balaban, A. T.; Schroth, W.;
Fischer, G. W. Pyrylium salts. In Advances in Heterocyclic Chemistry; A. R. Katritzky
(Ed.); Academic: New York, 1969, vol. 10, p. 241, and references therein.

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