Thermally-induced ring contraction as a novel and straightforward route for the synthesis of 2-furyl acetonitrile derivatives

Article abstract of DOI:10.1016/j.tetlet.2013.03.033

A new, efficient, and simple process has been established for the synthesis of (3,5-diaryl-2-furyl)(aryl)acetonitriles by the reaction of various 2,4,6-triarylpyrylium perchlorates with sodium cyanide.

Full text of DOI:10.1016/j.tetlet.2013.03.033

Tetrahedron Letters 54 (2013) 2641–2644
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Tetrahedron Letters
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Thermally-induced ring contraction as a novel and straightforward route
for the synthesis of 2-furyl acetonitrile derivatives
⇑
Arash Mouradzadegun , Fatemeh Abadast
Department of Chemistry, Faculty of Science, Shahid Chamran University, Ahvaz, Iran
a r t i c l e i n f o
a b s t r a c t
Article history:
A
new, efficient, and simple process has been established for the synthesis of (3,5-diaryl-2-
Received 29 January 2013
Revised 25 February 2013
Accepted 7 March 2013
Available online 15 March 2013
furyl)(aryl)acetonitriles by the reaction of various 2,4,6-triarylpyrylium perchlorates with sodium cyanide.
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
2-Furyl acetonitrile
Pyrylium salts
Nucleophilic reaction
Ring contraction
Furan derivatives occur widely as essential structural units in a
variety of natural products.1 They are also present in commercially
important products such as agrochemical bioregulators, dyes and
photosensitizers, essential oils, and flavoring and fragrance com-
pounds.2 Moreover, the utility of this moiety as a building block
and intermediate3 in synthesis has received considerable atten-
tion,4 in addition to their wide range of biological activities.5
Among them, 2-furyl acetonitrile derivatives have found use as
key intermediates toward the fatty acid derivatives, plakorsins A
and B,6 isolated from the marine sponge, Plakortis simplex,7 which
demonstrate useful cytotoxic activities against various cancer cell
lines.
Due to the aforementioned chemical and pharmacological
significance, the development of direct and convenient methods
to generate furan derivatives from simple, readily available start-
ing materials has attracted considerable interest.8 Although a vari-
ety of strategies have been reported in this area,9 most methods
suffer from one or more drawbacks such as long reaction times,
multiple steps, the use of expensive transition metal catalysts,
and harsh reaction conditions. Therefore, further improvements
are required for the synthesis of these molecules.
synthesis of 2-furyl acetonitrile derivatives. In continuation of our
studies on the development of practical and eco-friendly proce-
dures for various important reactions and transformations,11
herein, we report for the first time, the applicability of thermally-
induced ring contractions for the convenient synthesis of 2-furyl
acetonitrile derivatives from the readily accessible corresponding
pyrylium salts.
2,4,6-triarylpyrylium perchlorates were easily synthesized from
the corresponding aldehydes and ketones by the previously
described method10,12 (Scheme 1).
To develop suitable reaction conditions, 2,4,6-triphenylpyryli-
um perchlorate was chosen as a model compound and parameters
including solvent, temperature, and molar ratio of the reagent and
substrate were examined in detail.
Y
CHO
Y
H2SO4, heat
EtOH, HClO4
Pyrylium salts represent, more so than other heterocyclic
systems, a nodal point for many synthetic routes as they can func-
tion as intermediates for a very wide variety of syntheses.10 They
owe their key role to their reactivity toward nucleophiles.
Despite many advances in the chemistry of pyrylium salts, there
have been no reports on the use of these salts as substrates for the
+
O
O
-
ClO4
X
X
2
X
1
X = H, OMe
Y = H, Me, NMe2, Cl
⇑
Corresponding author. Tel.: +98 611 3331042; fax: +98 611 3337009.
E-mail address: arash_m@scu.ac.ir (A. Mouradzadegun).
Scheme 1. Synthesis of 2,4,6-triarylpyrylium perchlorates 1.
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.03.033

2642
A. Mouradzadegun, F. Abadast / Tetrahedron Letters 54 (2013) 2641–2644
Ar2
Table 1
Ar2
1CN
Optimization of the reagent/substrate ratio
4
2
CH3CN
H
Ar1
Entry
Reagent/substrate
Time (min)
Yield of 3 (%)
5
6
3
NaCN
+
Ar1
O
Ar1
°
H
85 C, 3-12 min
Ar1
O
1
2
3
4
1
1.5
2
20
15
7
60
60
60
53
-
ClO4
2.5
5
1
2
1CN
2
O
Ar1
Ar1
3
6
5
a small amount of product 3. The formation of 3, which might oc-
cur through a cyanodienone intermediate, is of considerable inter-
est since it is the first example of ring contraction involving a
carbon nucleophile instead of the customarily applied nitrogen or
oxygen nucleophiles. The highest yield of product 3 was obtained
at reflux temperature. Hence, the reaction was run at reflux tem-
perature in all subsequent cases (Scheme 2).
Next, the reaction of model compound 1 (1 mmol) with varying
amounts of sodium cyanide was investigated. As shown in Table 1,
the target product was favored by increasing the reagent/substrate
ratio as indicated by the significant decrease in the reaction time.
Bearing in mind that the reaction proceeds through an addition/
ring-opening mechanism, the increase in reagent concentration fa-
vors the first reaction step and, on the whole, product formation.
The decrease in the yield (53%) employing a ratio of 2.5 (entry 4)
can probably be explained due to the generation of by-products.
The best yield (60%) and the shortest reaction time (7 min) were
obtained using a ratio of reagent/substrate = 2 (entry 3).
H
4
Ar2
3
Ar1 : C6H5, C6H4 p-OMe
Ar2 : C6H5, C6H4 p-Me, C6H4 p-NMe2, C6H4 p-Cl
Scheme 2. Synthesis of (3,5-diaryl-2-furyl)(aryl)acetonitriles 3 via the reaction of
various triarylpyrylium perchlorates 1 with NaCN.
Among the solvents investigated which included ethanol, tetra-
hydrofuran, dichloromethane, and acetonitrile, the best result in
terms of yield was obtained with acetonitrile.
The reaction was also evaluated at different temperatures. At
room temperature, the reaction of 2,4,6-triphenylpyrylium per-
chlorate 1 with sodium cyanide gave the corresponding cyanodie-
none 2 as the sole product. There was no evidence of the
transformation into 2-furyl acetonitrile 3 according to TLC analysis.
The facile nature of this reaction is testament to the high chemical
potential of the pyrylium nucleus which, despite its aromaticity, is
easily opened under such mild conditions. Surprisingly, raising the
temperature led to the formation of the cyanodienone 2 along with
The scope of this protocol was then investigated under the opti-
mized reaction conditions.13 Substituted 2,4,6-triarylpyrylium per-
chlorates (1 mmol) were subjected to the reaction with NaCN
(2 mmol) in acetonitrile (10 ml) under reflux conditions (Table 2).
Substrates with electron-donating groups led to decreased reaction
rates (entries A–D). This can be rationalized by considering the fact
that these groups decrease the positive charge at the a-position of
Table 2
The conversion of various triarylpyrylium salts into the corresponding (3,5-diaryl-2-furyl)(aryl)acetonitriles at 85 °C
Entry Substrate
Ph
Intermediate (2)
Product (3)
Time (min) Yield (%)
Ph
Ph
CN
Ph
O
Ph
O
O
CN
A
B
7
9
60
61
Ph
Ph
O
Ph
Ph
CN
Ph
C6H4(p-Me)
Ph
Ph
O
Ph
CN
O
Ph
C6H4(p-Me)
Me
(MeO_p)C6H4
C6H4(p_OMe)
CN
C6H4(p Me)
CN
C6H4(p-OMe)
O
(MeO -p)C6H4
O
C
D
E
10
12
3
71
66
60
C6H4(p OMe)
(MeO p)C6H4
O
C6H4(p-Me)
Me
Ph
CN
C6H4(p _NMe2)
Ph
O
CN
Ph
O
O
Ph
Ph
Ph
Ph
Ph
O
C6H4(p-NMe2)
NMe2
C6H4(p_Cl)
Ph
Ph
CN
Ph
O
CN
Ph
O
C6H4(p-Cl)
Cl

A. Mouradzadegun, F. Abadast / Tetrahedron Letters 54 (2013) 2641–2644
2643
Ar2
O
Ar2
CN
Ar1
H
Ar2
Ar2 CN
Ar1
O
NaCN
H1
Ar1
CN
Ar1
Ar1
Ar1
H
Ar1
O
°
CH3CN, 85 C
Ar1
O
-
ClO4
1
4
2
CN
O
Ar1
Ar1
Ar1 : C6H5, C6H4 p-OMe
Ar2 : C6H5, C6H4 p-Me, C6H4 p-NMe2, C6H4 p-Cl
Ar2
3
Scheme 3. A plausible mechanism for the formation of furan derivatives 3.
19, 2240; (c) Bateman, T. D.; Joshi, A. L.; Moona, K.; Galitovskaya, E. N.; Upreti,
M.; Chambers, T. C.; McIntosh, M. C. Bioorg. Med. Chem. Lett. 2009, 19, 6898; (d)
Cushman, M.; Sambaiah, T.; Jin, G.; Lllarionov, B.; Fischer, M.; Bacher, A. J. Org.
Chem. 2004, 69, 601; (e) Kim, S.; Kang, D.; Shin, S.; Lee, P. H. Tetrahedron Lett.
2010, 51, 1899.
the heterocyclic ring. The presence of stronger electron-donating
groups led to even longer reaction times. In contrast, an electron-
withdrawing group (entry E) accelerated the reaction.
The structures of compounds 2 and 3 were established unam-
biguously from physical and spectroscopic (IR, 1H NMR, 13C
NMR) data.
4. (a) Singh, R. P.; Foxman, B. M.; Deng, L. J. Am. Chem. Soc. 2010, 132, 9558; (b)
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Hou, X. L.; Cheung, H. Y.; Hon, T. Y.; Kwan, P. L.; Lo, T. H.; Tong, S. Y.; Wong, H.
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references therein.
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(b) Mross, G.; Holtz, E.; Langer, P. J. Org. Chem. 2006, 71, 8045; (c) Xu, B.;
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Q.; Liu, J. J. Org. Chem. 2008, 73, 7625; (e) Zhao, L. B.; Guan, Z. H.; Han, Y.; Xie, Y.
X.; He, S.; Liang, Y. M. J. Org. Chem. 2007, 72, 10276; (f) Kuninobu, Y.; Nishina,
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3756; (h) Blanc, A.; Tenbrink, K.; Weibel, J. M.; Pale, P. J. Org. Chem. 2009, 74,
5342.
On the basis of the results obtained above, a potential reaction
mechanism involves the formation of
a-cyanopyran 4 in the first
step, which is readily converted into cyanodienone 2 through a
tautomeric process (Scheme 3). It is postulated that this non-
aromatic product is the common intermediate which in turn
undergoes ring-closure and hydrogen abstraction to give 2-furyl
acetonitrile derivatives 3. This assumption was proved by isolating
the cyanodienone intermediates and subjecting them to direct
conversion into the 2-furyl acetonitriles on heating.
In summary, we have described a new, direct, and reliable
thermally-induced ring contraction pathway for the synthesis of
several 2-furyl acetonitrile derivatives. To the best of our knowl-
edge, this is the first example of the formation of 2-furyl acetoni-
trile products starting from pyrylium salts. We anticipate that
this new and viable route should be useful to both research and
pharmaceutical development endeavors.
Acknowledgment
This work was supported by the Research Council of the Univer-
sity of Shahid Chamran.
10. Balaban, A. T.; Dinculescu, A.; Dorofeenko, G. N.; Fischer, G. W.; Koblik, A. V.;
Mezheritskii, V. V.; Schroth, W. In Advances in Heterocyclic Chemistry; Katritzky,
A. R., Ed.; Academic Press: New York, 1982; Vol. 2,. Suppl. 1.
11. (a) Mouradzadegun, A.; Gheitasvand, N. Phosphorus, Sulfur Silicon Relat. Elem.
2005, 180, 1385; (b) Ganjali, M. R.; Norouzi, P.; Emami, M.; Golmohamadi, M.;
Pirelahi, H.; Mouradzadegun, A. J. Chin. Chem. Soc. 2006, 53, 1209; (c) Ganjali,
M. R.; Akbar, V.; Daftari, A.; Norouzi, P.; Pirelahi, H.; Mouradzadegun, A. J. Chin.
Chem. Soc. 2004, 51, 309; (d) Mouradzadegun, A.; Pirelahi, H. J. Photochem.
Photobiol., A: Chem. 2001, 138, 203; (e) Mouradzadegun, A.; Pirelahi, H.
Phosphorus, Sulfur Silicon Relat. Elem. 2000, 165, 149; (f) Mouradzadegun, A.;
Pirelahi, H. Phosphorus, Sulfur Silicon Relat. Elem. 2000, 157, 193; (g)
Mouradzadegun, A.; Dianat, Sh. J. Heterocycl. Chem. 2009, 46, 778; (h)
Mouradzadegun, A.; Ghasem Hezave, F.; Karimnia, M. Phosphorus, Sulfur
Silicon Relat. Elem. 2010, 185, 84; (i) Mouradzadegun, A.; Abadast, F. Monatsh.
Chem. 2013, 144, 375.
A. Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2013.03.
033.
References and notes
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Chemistry of Heterocycles: Structure, Reactions, Syntheses, and Applications;
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Prod. Rep. 2006, 17, 235; (b) Zanatta, N.; Alves, S. H.; Coelho, H. S.; Borchhardt,
D. M.; Machado, P.; Flores, K. M.; da Silva, F. M.; Spader, T. B.; Santurio, J. M.;
Bonacorso, H. G.; Martins, M. A. P. Bioorg. Med. Chem. 2007, 15, 1947.
3. (a) Maier, M. In Organic Synthesis Highlights II; Waldmann, H., Ed.; VCH:
Weinheim, 1995; p 231; (b) Lavieri, R.; Scott, S. A.; Lewis, J. A.; Selvy, P. E.;
Armstrong, M. D.; Alex Brown, H.; Lindsley, C. W. Bioorg. Med. Chem. Lett. 2009,
12. Balaban, A. T.; Schroth, W.; Fischer, G. W. Pyrylium Salts In Advances in
Heterocyclic Chemistry; Katritzky, A. R., Ed.; Academic Press: New York, 1969;
Vol. 10, p 241. and references therein.
13. General procedure for the synthesis of 3: The triarylpyrylium perchlorate 1
(1 mmol) was dissolved in MeCN (10 ml), NaCN (2 mmol) was added and
mixture refluxed for 3–12 min. After completion of the reaction, the solvent
was evaporated under vacuum and the residue was adsorbed on silica,
transferred to a silica column and eluted with a 20:80 mixture of Et2O:n-
hexane. The obtained product was recrystallized from EtOH. (2Z,4E)-6-Oxo-
2,4,6-triphenyl-2,4-hexadienenitrile (2A). Yield 78%; yellow crystals, mp 103–
105 °C (from EtOH); IR (neat):
m ;
2218 (CN), 1645 (CO) cmÀ1 1H NMR
(400 MHz, CDCl3): d 7.33 (s, 1H, H-1), 7.45–8.05 (m, 15H, Ar-H), 8.4 (s, 1H, H-2)
ppm; 13C NMR (100 MHz, CDCl3): d 115.9 (C-2), 119.6 (C-1), 126.2 (C-5), 126.9,

2644
A. Mouradzadegun, F. Abadast / Tetrahedron Letters 54 (2013) 2641–2644
128.8, 129.1, 129.2, 129.4, 129.5, 130.3, 130.6, 133.6 (ArC), 134.1, 138.8, 139.4
5.5 (s, 1H, H-1), 6.8 (s, 1H, H-2), 7.3–7.7 (m, 15H, Ar-H) ppm; 13C NMR
(100 MHz, CDCl3): d 35.4 (C-2), 107.4 (C-5), 117.3 (C-1), 124.4 (ArC), 127.3 (C-
4), 127.8–129.6 (ArC), 130.2, 132.5, 133.9 (ArCq), 141.6 (C-3), 154.8 (C-6) ppm.
(ArCq), 141.8 (C-3), 151.9 (C-4), 190.6 (C-6) ppm. (3,5-Diphenyl-2-
furyl)(phenyl)acetonitrile (3A). Yield 60%; white crystals, mp 85 °C (from
EtOH); [M+] = 335; IR (neat):
m ;
2245 (CN) cmÀ1 1H NMR (400 MHz, CDCl3): d