Multicomponent synthesis of a new series of 4H-furo[3,4-b]pyrans, with iron(III) triflate as catalyst

Article abstract of DOI:10.1007/s11164-014-1585-x

We report the first efficient multicomponent reaction, catalyzed by iron(III) triflate, for synthesis of a new series of functionalized 4H-furo[3,4-b]pyran derivatives.

Full text of DOI:10.1007/s11164-014-1585-x

Res Chem Intermed
DOI 10.1007/s11164-014-1585-x
Multicomponent synthesis of a new series of
4H-furo[3,4-b]pyrans, with iron(III) triflate as catalyst
•
•
•
Reza Sandaroos Alireza Nazif Hamidreza Molaei
Saeid Salimi
Received: 30 November 2013 / Accepted: 5 March 2014
Ó Springer Science+Business Media Dordrecht 2014
Abstract We report the first efficient multicomponent reaction, catalyzed by
iron(III) triflate, for synthesis of a new series of functionalized 4H-furo[3,4-b]pyran
derivatives.
Keywords Multicomponent synthesis Á Furo[3,4-b]pyran Á Catalyst
Introduction
Because multicomponent reactions have several inherent advantages over two-compo-
nent reactions, for example the simplicity of one-pot procedures, possible structure
variations, complicated synthesis, and the large number of accessible compounds [1],
efforts continue to investigate new MCRs to replace popular organic reactions [2].
Pyran derivatives are an important class of compounds with excellent
photochromic properties [3]. Many biologically active compounds contain the
pyran structure [4], and pyran derivatives are used for drug synthesis because of
their varied pharmacological and biological activity, for example antimicrobial,
mutagenic, antiproliferative, and antitumor; use of pyran derivatives in cancer
therapy [5] has also been reported. Hu and coworkers [6] synthesized pyrano[3,2-
c]quinolinone derivatives. Shaabani et al. [7] reported the synthesis of 4H-furo[3,4-
b]pyran compounds via three-component reaction of an isocyanide, a dialkyl
acetylenedicarboxylate, and tetronic acid in dichloromethane at room temperature.
Synthesis of 4H-furo[2,3-b]pyran compounds by reaction of 3-arylmethylene-3H-
furan-2-ones with malononitrile has been studied by Aniskova and Yegorova [8].
R. Sandaroos (&) Á S. Salimi
Department of Chemistry, Faculty of Science, University of Birjand, Birjand, Iran
e-mail: R_Sandaroos@yahoo.com
R. Sandaroos Á A. Nazif Á H. Molaei (&) Á S. Salimi
Young Researchers and Elite Club, Sarvestan Branch, Islamic Azad University, Fars, Iran
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R. Sandaroos et al.
R
O
O
O
O
O
Fe(OTf)3
CH2(CN)2
CN
+
+
H
CH3CN
7h
O
O
NH2
R
R= H- (1) (84%); p-OMe- (2) (80%); p-NO2 (3)- (92%); p-Br- (4) (90%); P-Me- (5)
(78%); p-Cl (6) (87%); p-CN- (7) (88%); o-NO2 (8) (90%); o-Cl- (9) (88%); p-F- (10)
(88%); 2,6-Cl (11) (88%), 2-thienyl (12) (72%).
Scheme 1 Synthesis of a series of 4H-furo[3,4-b]pyran compounds
One-step synthesis of 4H-furo[3,4-b]pyrans by reaction of 2,4(3H,5H)-furandione
(b-tetronic acid) with arylmethylenemalononitriles in basic medium has been
reported by Martin et al. [9].
Metal triflates (trifluoromethylsulfonates) have been found to be unique Lewis
acids. They are water-tolerant, reusable catalysts which effectively promote several
carbon–carbon and carbon–heteroatom bond-forming reactions in good yields [10].
In recent years the outstanding potential of these catalysts has led to much research
endeavor [11]. Our continued interest in developing synthetic methodology using
Lewis acid and triflate salts [12–14] prompted us to investigate the utility of
iron(III) triflate as an efficient catalyst for MCR reaction of tetronic acid, aromatic
aldehyde, and malononitrile as a novel procedure for preparation of a series of
2-amino-5,7-dihydro-5-oxo-4-aryl-4H-furo[3,4-b]pyran-3-carbonitrile derivatives
(Scheme 1).
Experimental
General
All products are new, and were characterized by IR and 1H NMR spectroscopy and
1
elemental analysis. H NMR (100 MHz) spectra were recorded on a Bruker AQS
Avance-100 spectrometer in CDCl3, with TMS as internal standard. IR spectra were
recorded using KBr disks on a FT-IR Bruker Tensor spectrometer. Elemental
analysis was performed by use of a Heraeus CHNO-type analyzer. Thin-layer
chromatography (TLC) on commercial aluminium-backed silica gel 60 F254 plates
was used to monitor the progress of reactions.
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Multicomponent synthesis of new series of 4H-furo[3,4-b]pyrans
General procedure for preparation of 4-aryl-4H-furo[3,4-b]pyran-3-carbonitrile
(1–10)
Fe(CF3SO3)3 (15 mol%) was added to a solution of tetronic acid (1 mmol),
aromatic aldehyde (1 mmol), and malononitrile (1.1 mmol) in dry acetonitrile
(10 ml). The reaction mixture was stirred at reflux temperature and monitored by
TLC until the disappearance of starting material. The solvent was then evaporated
and the residue was diluted with dichloromethane (10 ml) and water (15 ml). The
organic phase was separated and the aqueous layer was washed with dichloro-
methane (10 ml). Concentration of the combined organic layer under reduced
pressure afforded the crude product, which was purified by neutral silica gel column
chromatography to afford the corresponding 4H-furo[3,4-b]pyrans. The aqueous
layer containing Fe(OTf)3 in the above work-up procedure was separated and
evaporated under reduced pressure to afford the crude catalyst. The resulting solid
residue was dried at 70 °C for 2 h to give the pure catalyst (recovery 90 %).
2-Amino-5,7-dihydro-5-oxo-4-phenyl-4H-furo[3,4-b]pyran-3-carbonitrile (1)
IR (KBr, mmax, cm-1): 3385 and 3287 (asym. and sym. str. of –NH2), 2112 (–CN
str.), 1742 (C=O), 1255 (asym. str. of cyclic Ar C–O–C ether). 1H NMR (100 MHz,
CDCl3) dH (ppm): 4.88 (d, 1H, J = 7 Hz, CH–H), 4.94 (d, 1H, J = 7 Hz, CH–H),
5.80 (s, 1H, CH), 6.77 (brs, 2H, D2O exch., NH2), 7.40–7.05 (m, 5H, ArH). Anal
Calcd for C14H10N2O3: C, 66.14; H, 3.96; N, 11.02 %. Found: C, 67.28; H, 4.07; N,
10.88 %.
2-Amino-5,7-dihydro-4-(4-methoxyphenyl)-5-oxo-4H-furo[3,4-b]pyran-3-
carbonitrile (2)
IR (KBr, mmax, cm-1): 3410 and 3275 (asym. and sym. str. of –NH2), 2124 (–CN
str.), 1735 (C=O), 1260 (asym. str. of cyclic Ar C–O–C ether). 1H NMR (100 MHz,
CDCl3) dH (ppm): 3.55 (s, 3H, OCH3), 4.83 (d, 1H, J = 6 Hz, CH–H), 4.95(d, 1H,
J = 6 Hz, CH–H), 6.84 (brs, 2H, D2O exch., NH2), 5.61 (s, 1H, CH), 7.20 (dd, 2H,
4
3
4
3J = 6 Hz, J = 2 Hz, ArH), 7.35 (dd, 2H, J = 6 Hz, J = 2 Hz, ArH). Anal
Calcd for C15H12N2O4: C, 63.38; H, 4.25; N, 9.85 %. Found: C, 64.44; H, 4.47; N,
9.77 %.
2-Amino-5,7-dihydro-4-(4-nitrophenyl)-5-oxo-4H-furo[3,4-b]pyran-3-carbonitrile
(3)
IR (KBr, mmax, cm-1): 3412 and 3190 (asym. and sym. str. of –NH2), 2156 (–CN
str.), 1738 (C=O), 1384 and 1545 (asym. and sym. str. of –NO2), 1251 (asym. str. of
1
cyclic Ar C–O–C ether). H NMR (100 MHz, CDCl3) dH (ppm): 4.81 (d, 1H,
J = 7 Hz, CH–H), 4.93 (d, 1H, J = 7 Hz, CH–H), 5.60 (s, 1H, CH), 6.85 (brs, 2H,
D2O exch., NH2), 7.35 (dd, 2H, 3J = 5 Hz, 4J = 1 Hz, ArH), 7.65 (dd, 2H,
4
3J = 5 Hz, J = 1 Hz, ArH). Anal Calcd for C14H9N3O5: C, 56.19; H, 3.03; N,
14.04 %. Found: C, 57.11; H, 3.08; N, 14.11 %. MS: m/z 299 (M?).
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R. Sandaroos et al.
2-Amino-4-(4-bromophenyl)-5,7-dihydro-5-oxo-4H-furo[3,4-b]pyran-3-carbonitrile
(4)
IR (KBr, mmax, cm-1): 3405 and 3251 (asym. and sym. str. of –NH2), 2207 (–CN
str.), 1742 (C=O), 1257 (asym. str. of cyclic Ar C–O–C ether). 1H NMR (100 MHz,
CDCl3) dH (ppm): 4.88 (d, 1H, J = 8 Hz, CH–H), 4.99 (d, 1H, J = 8 Hz, CH–H),
5.53 (s, 1H, CH), 6.85 (brs, 2H, D2O exch., NH2), 7.10 (dd, 2H, 3J = 6 Hz,
4J = 2 Hz, ArH), 7.63 (dd, 2H, 3J = 6 Hz, 4J = 2 Hz, ArH). Anal Calcd for
C14H9BrN2O3: C, 50.47; H, 2.72; N, 8.41 %. Found: C, 52.03; H, 2.80; N, 8.48 %.
2-Amino-5,7-dihydro-5-oxo-4-p-tolyl-4H-furo[3,4-b]pyran-3-carbonitrile (5)
IR (KBr, mmax, cm-1): 3420 and 3275 (asym. and sym. str. of –NH2), 2185 (–CN
str.), 1736 (C=O), 1252 (asym. str. of cyclic Ar C–O–C ether). 1H NMR (100 MHz,
CDCl3) dH (ppm): 2.34 (s, 3H, Ar–CH3), 4.82 (d, 1H, J = 7 Hz, CH–H), 4.94 (d,
1H, J = 7 Hz, CH–H), 5.58 (s, 1H, CH), 6.80 (brs, 2H, D2O exch., NH2), 7.24–7.05
(m, 4H, ArH). Anal Calcd for C15H12N2O3: C, 67.16; H, 4.51; N, 10.44 %. Found:
C, 66.88; H, 4.43; N, 10.75 %.
2-Amino-4-(4-chlorophenyl)-5,7-dihydro-5-oxo-4H-furo[3,4-b]pyran-3-carbonitrile
(6)
IR (KBr, mmax, cm-1): 3410 and 3262 (asym. and sym. str. of –NH2), 2133 (–CN
str.), 1742 (C=O), 1247 (asym. str. of cyclic Ar C–O–C ether). 1H NMR (100 MHz,
CDCl3) dH (ppm): 4.85 (d, 1H, J = 6 Hz, CH–H), 4.94 (d, 1H, J = 6 Hz, CH–H),
5.55 (s, 1H, CH), 6.77 (brs, 2H, D2O exch., NH2), 7.18 (dd, 2H, 3J = 5 Hz,
4J = 2 Hz, ArH), 7.60 (dd, 2H, 3J = 5 Hz, 4J = 2 Hz, ArH). Anal Calcd for
C14H9ClN2O3: C, 58.25; H, 3.14; N, 9.70 %. Found: C, 57.23; H, 3.19; N, 9.91 %.
2-Amino-4-(4-cyanophenyl)-5,7-dihydro-5-oxo-4H-furo[3,4-b]pyran-3-carbonitrile
(7)
IR (KBr, mmax, cm-1): 3404 and 3215 (asym. and sym. str. of –NH2), 2206 (–CN
str.), 2176 (–CN str.), 1741 (C=O), 1255 (asym. str. of cyclic Ar C–O–C ether). H
1
NMR (100 MHz, CDCl3) dH (ppm): 4.87 (d, 1H, J = 6 Hz, CH–H), 4.96 (d, 1H,
J = 6 Hz, CH–H), 5.50 (s, 1H, CH), 6.55 (brs, 2H, D2O exch., NH2), 7.22 (dd, 2H,
4
3
4
3J = 6 Hz, J = 2 Hz, ArH), 7.48 (dd, 2H, J = 6 Hz, J = 2 Hz, ArH). Anal
Calcd for C15H9N3O3: C, 64.52; H, 3.25; N, 15.05 %. Found: C, 66.09; H, 3.33; N,
15.18 %.
2-Amino-5,7-dihydro-4-(2-nitrophenyl)-5-oxo-4H-furo[3,4-b]pyran-3-carbonitrile
(8)
IR (KBr, mmax, cm-1): 3410 and 3267 (asym. and sym. str. of –NH2), 2206 (–CN
str.), 2176 (–CN str.), 1382 and 1547 (asym. and sym. str. of –NO2), 1742 (C=O),
1253 (asym. str. of cyclic Ar C–O–C ether). 1H NMR (100 MHz, CDCl3) dH (ppm):
123

Multicomponent synthesis of new series of 4H-furo[3,4-b]pyrans
4.87 (d, 1H, J = 6 Hz, CH–H), 4.98 (d, 1H, J = 6 Hz, CH–H), 5.50 (s, 1H, CH),
6.55 (brs, 2H, D2O exch., NH2), 7.30 (m, 2H, Ar–H), 7.60 (m, 1H, Ar–H), 8.01 (dd,
1H, 3J = 5 Hz, 4J = 1 Hz, ArH). Anal Calcd for C14H9N3O5: C, 56.19; H, 3.03; N,
14.04 %. Found: C, 55.73; H, 3.10; N, 13.93 %.
2-Amino-4-(2-chlorophenyl)-5,7-dihydro-5-oxo-4H-furo[3,4-b]pyran-3-carbonitrile
(9)
IR (KBr, mmax, cm-1): 3412 and 3260 (asym. and sym. str. of –NH2), 2214 (–CN
str.), 1745 (C=O), 1244 (asym. str. of cyclic Ar C–O–C ether). 1H NMR (100 MHz,
CDCl3) dH (ppm): 4.81 (d, 1H, J = 7 Hz, CH–H), 4.96 (d, 1H, J = 7 Hz, CH–H),
5.63 (s, 1H, CH), 6.73 (brs, 2H, D2O exch., NH2), 7.57–7.14 (m, 4H, ArH). Anal
Calcd for C14H9ClN2O3: C, 58.25; H, 3.14; N, 9.70 %. Found: C, 57.64; H, 3.18; N,
9.83 %.
2-Amino-4-(4-fluorophenyl)-5,7-dihydro-5-oxo-4H-furo[3,4-b]pyran-3-carbonitrile
(10)
IR (KBr, mmax, cm-1): 3401 and 3212 (asym. and sym. str. of –NH2), 2203 (–CN
str.), 1740 (C=O), 1242 (asym. str. of cyclic Ar C–O–C ether). 1H NMR (100 MHz,
CDCl3) dH (ppm): 5.44 (s, 1H, CH), 4.88–4.80 (m, 2H, CH2), 6.71 (brs, 2H, D2O
exch., NH2), 7.67 (d, 2H, Ar–H), 7.81 (d, 2H, Ar–H). Anal Calcd for C14H9FN2O3:
C, 61.77; H, 3.33; N, 10.29 %. Found: C, 62.02; H, 3.38; N, 10.17 %.
2-Amino-4-(2,6-dichlorophenyl)-5,7-dihydro-5-oxo-4H-furo[3,4-b]pyran-3-
carbonitrile (11)
IR (KBr, mmax, cm-1): 3412 and 3220 (asym. and sym. str. of –NH2), 2211 (–CN
str.), 1736 (C=O), 1236 (asym. str. of cyclic Ar C–O–C ether). 1H NMR (100 MHz,
CDCl3) dH (ppm): 4.95 (s, 1H, CH), 4.90–4.82 (m, 2H, CH2), 6.80 (brs, 2H, D2O
exch., NH2), 7.26–7.65 (m, 3H, Ar–H). Anal Calcd for C14H8Cl2N2O3: C, 52.04; H,
2.50; N, 8.67 %. Found: C, 52.78; H, 2.82; N, 8.81 %.
2-Amino-4-(2-thienyl)-5,7-dihydro-5-oxo-4H-furo[3,4-b]pyran-3-carbonitrile (12)
IR (KBr, mmax, cm-1): 3425 and 3222 (asym. and sym. str. of –NH2), 2214 (–CN
str.), 1747 (C=O), 1248 (asym. str. of cyclic Ar C–O–C ether). 1H NMR (100 MHz,
CDCl3) dH (ppm): 4.83 (s, 1H, CH), 4.90–5.02 (m, 2H, CH2), 6.80 (brs, 2H, D2O
exch., NH2), 6.95–7.52 (m, 3H). Anal Calcd for C12H8N2O3S: C, 55.38; H, 3.10; N,
10.76 %. Found: C, 55.33; H, 3.08; N, 10.72 %.
Results and discussion
First, a mixture of tetronic acid, 4-nitrobenzaldehyde, and malononitrile was chosen
as model reaction to determine whether Fe(OTf)3 was an efficient catalyst. The
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R. Sandaroos et al.
Isolated yield (%)a
Table 1 Efficiency of the catalysts used for synthesis of compound (3)
Entry
Catalyst
Time (h)
1
2
3
4
a
Zn(OTf)2
7
7
7
7
78
74
70
92
Cu(OTf)2
Triflic acid (HOTf)
Fe(OTf)3
Reaction conditions: CH3CN (10 ml), catalyst 15 mol%, reflux
reaction mixture was stirred at reflux temperature in acetonitrile with 5 mol%
catalyst for 7 h and the corresponding 2-amino-5,7-dihydro-4-(4-nitrophenyl)-5-
oxo-4H-furo[3,4-b]pyran-3-carbonitrile (3 in Scheme 1) was obtained in 92 %
yield. No target product was observed when the mixture was stirred under similar
conditions in the absence of Fe(OTf)3, even after prolonged reaction time,
demonstrating the effect of Fe(OTf)3 as catalyst. Next, the amount of the iron triflate
used was varied from 5 to 20 mol%. The results showed that the yield of the
reaction improved when the amount of catalyst was increased from 5 (84 % yield)
to 15 mol% (92 % yield). However, the yield was minimally affected when the
amount of Fe(OTf)3 was further increased from 15 to 20 mol%. Therefore,
15 mol% of the catalyst was considered to be suitable. It is worth reporting that
other metal triflates available in our laboratory were also investigated in an attempt
to further optimize the reaction. The ferric catalyst Fe(OTf)3 was the most effective;
the catalytic efficiency of Zn(OTf)2, Cu(OTf)2 and triflic acid (HOTf) was lower—
78, 74 and 70 %, respectively (Table 1). The recyclability of Fe(OTf)3 was also
investigated. The catalyst could be reused four times without any significant loss of
its activity. Yields were 84, 83, and 81 % for subsequent runs 2, 3, and 4,
respectively indicating high reusability of the catalyst.
Having established the optimized reaction conditions, these were used for
reaction of a variety of aromatic aldehydes with diverse electronic features, to
investigate the generality of the procedure. The results are shown in Scheme 1. All
the reactions were conducted under reflux for 7 h. The nature of the substituents on
the aromatic ring had no substantial effect on the efficiency of the reaction, although
electron-withdrawing substituents slightly increased the chemical yield. The
experimental procedure is very efficient, convenient, and has the ability to tolerate
a variety of other functional groups, for example methoxy, nitro, and halides under
these reaction conditions.
Mode of action of the catalyst
Iron triflate is a strong Lewis acid because the ferric ion has an empty 3d orbit and
trifluoromethylsulfonates are strongly electron-withdrawing. Indeed, the triflate anion
is both weakly nucleophilic and coordinating, rendering the metal counterion more
cationic and thus a stronger Lewis acid. It can activate the carbonyl group of carbonyl
compounds, facilitating cross-coupling between tetronic acid and aromatic aldehyde,
which results in the formation of a,b-unsaturated compound A. Enolization of
123

Multicomponent synthesis of new series of 4H-furo[3,4-b]pyrans
CN
NC
O
O
O
O
Ar
N
Ar
O
O
O
Ar
CN
OH
O
NC
B
N
Fe(III)
Fe(III)
A
O
O
Ar
H
Ar
O
O
CN
CN
NH2
O
O
N
D
C
H
Scheme 2 Proposed mechanism for the synthesis of 2-amino-5,7-dihydro-5-oxo-4-aryl-4H-furo[3,4-
b]pyran-3-carbonitrile derivatives
compound B is also accelerated by Fe(OTf)3. In addition, the catalyst is capable of
binding with the nitrogen atom of nitrile group to catalyze the final heterocyclization
process.
This catalyst has several advantages over the other Lewis acids. Because it is
stable in water it does not decompose during the aqueous work-up procedure, so its
recycling is possible without substantial loss of activity. As a result this procedure
environmentally acceptable.
Mechanism
Accordingly, a probable mechanism for the synthesis of furo[3,4-b]pyran deriva-
tives may be postulated as shown in Scheme 2. The first step of the reaction
involves nucleophilic attack of tetronic acid on the carbonyl group of the aldehyde
resulting in C-alkylation to form the intermediate a,b-unsaturated compound
A. Michael type addition of malononitrile to A provides B. Enolization of the
intermediate B leads to its cyclization via nucleophilic attack of the O atom on the
cyano group, forming the iminopyran C which, on rearrangement, furnishes the
corresponding furo[3,4-b]pyran product D.
Conclusion
In summary, we report the first example of an efficient MCR synthesis of 2-amino-
5,7-dihydro-5-oxo-4-aryl-4H-furo[3,4-b]pyran-3-carbonitrile compounds catalyzed
123

R. Sandaroos et al.
by Fe(OTf)3. These new functionalized 4H-furo[3,4-b]pyran compounds may prove
of interest for biomedical screening.
References
1. I. Domling, Angew. Chem. Int. Ed. 39, 3168 (2000)
2. N.M. Evdokimov, I.V. Magedov, A.S. Kireev, A. Kornienko, Org. Lett. 8, 899 (2006)
3. N. Malic, J.A. Campbell, R.A. Evans, Macromolecules 41, 1206 (2008)
4. A.V. Karnik, A.M. Kulkarni, N.J. Malviya, B.R. Mourya, B.L. Jadhav, Eur. J. Med. Chem. 43, 2615
(2008)
5. W. Wang, W. Cheng, L. Shao, J. Yang, Catal. Lett. 121, 77 (2008)
6. M. Lei, L. Mab, L. Hu, Tetrahedron Lett. 52, 2597 (2001)
7. A. Shaabani, E. Soleimani, A. Sarvary, A.H. Rezayan, Chem. Lett. 15, 3968 (2008)
8. T.V. Aniskova, A.Y. Yegorova, Chem. Heterocycl. Compd. 45, 6 (2009)
9. N. Martin, J.L. Segura, C. Seoane, J.L. Soto, M. Morales, M. Margarita, M. Suarez, Liebigs Ann.
Chem. 8, 827 (1991)
10. S. Kobayashi, M. Sugiura, H. Kitagawa, W. Lam, Chem. Rev. 102, 2227 (2002)
11. M. Santelli, J.M. Pons, Lewis Acids and Selectivity in Organic Synthesis (CRC Press, Boca Raton,
1995)
12. S. Damavandi, R. Sandaroos, Res. Chem. Intermed. (2012). doi:10.1007/s11164-012-0681-z
13. S. Damavandi, R. Sandaroos, Res. Chem. Intermed. 38, 969 (2012)
14. R. Sandaroos, S. Damavandi, M. Salimi, A. Mohammadi, A. Karimian, M. Hasanpour, Mol. Divers.
16, 269 (2012)
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