Organic Letters
Letter
provided moderate yield of 13a (Table 1, entry 10). Aiming at
the identification of a more cost-effective and readily accessible
catalytic system, we tested various Fe-derived salts such as
Fe2(SO4)3·xH2O, FeCl3, FeBr3, and Fe2O3. Gratifyingly, 15
mol % of Fe2(SO4)3·xH2O in toluene at reflux delivered the
desired product in the best isolated yield of 87% in 6 h (Table
1, entry 4). Changing the reaction solvent from toluene to
ethyl acetate and chloroform showed a detrimental effect on
the yield (Table 1, entries 16 and 18). However, interesting
transformations happened when ethanol and THF were used.
In ethanol, the detected product was mostly a 1:2
condensation bisfuran product 16 (Scheme 2), whereas in
THF, the isolated product was a nonsymmetric triarylmethane
14a (Table 2). Due to its high reactivity, stability, natural
abundance, and cost-effectiveness, Fe2(SO4)3·xH2O was
chosen as a prominent catalyst for this work instead of the
closely competent but quite expensive Sc(OTf)3. Finally, the
optimized reaction conditions were selected as follows:
benzaldehyde (1 mmol), 2-methylfuran (1 mmol), and 4-
hydroxycoumarin (1 mmol) with Fe2(SO4)3·xH2O (15 mol %)
in toluene at reflux for 6 h. A plausible mechanism for the
above transformation has been included in the Supporting
Scheme 1. Diverse Synthetic Routes to Functionalized
Furo[3,2,-c]coumarins and Furo[3,2,-c]pyran-4-ones
Having optimized the reaction conditions, we consequently
expanded the substrate scope to the synthesis of several 2,3-
disubstituted furo[3,2,-c]coumarins 13a−n (Table 2). Aryl
aldehydes having electron-donating p-methyl 13b, p-methoxy
13c, or electron-withdrawing p-NO2 13d gave the sole
furo[3,2,-c]coumarins in good yields. Electronegative func-
tional o-bromo- and p-fluoro-substituents were also found to
be suitable for this domino reaction of 13e and 13f. A range of
linear and branched alkyl aldehydes, such as propionaldehyde,
butyraldehyde, valeraldehyde, and isobutyraldehyde, afforded
the corresponding products 13g−j in moderate to good yield.
The versatility of the Fe-catayzed domino reaction was
further explored with a sterically hindered aromatic aldehyde,
1-napthaldehyde, and a cyclic aldehyde, cyclohexanaldehyde.
Both aldehydes underwent intramolecular ring opening
smoothly to afford the furo[3,2,-c]coumarin products 13k
and 13l. In addition, heteroaryl rings such as thiophene and
piperonal (heliotropin) were also found to be suitable for this
domino reaction to afford corresponding products 13m and
13n in notable yield. The structure of the furo[3,2,-c]coumarin
products was confirmed through the internally consistent
spectral data and single-crystal X-ray structure determination
tion of 2,3-disubstituted furo[3,2,-c]coumarins and furo[3,2,-
c]pyran-4-ones through an iron-catalyzed domino reaction for
the synthesis of annulated heterocycles is not yet reported. In
this communication, we report a convenient and efficient
domino synthesis of Fe-catalyzed 2,3-disubstituted furo[3,2,-
c]coumarins and furo[3,2,-c]pyran-4-ones via nonsymmetric
triarylmethanes as a strategic intermediate (Scheme 1).
Intrigued by the initial results, optimization of the reaction
conditions was pursued by modifying parameters such as
solvent, temperature, catalyst, and reaction time (Table 1). We
began our investigation using commercially available 4-
hydroxycoumarin 10 (1 mmol), 2-methylfuran 11 (1 mmol),
and benzaldehyde 12a (1 mmol), with Fe2(SO4)3·xH2O (5
mol %, 20 mg) in toluene at room temperature for 24 h. The
desired product, 2,3-disubstituted furo[3,2,-c]coumarin 13a,
was isolated in 46% yield (Table 1, entry 2). Significant
improvement in yield (87%) was achieved by increasing the
amount of Fe2(SO4)3·xH2O to 15 mol % in toluene under
reflux conditions (Table 1, entry 4).
Under the optimized condition, reaction of 10, 11, and
12a−n undergoes a domino reaction to give furo[3,2,-
c]coumarins via unisolable nonsymmetric triarylmethanes.
However, we were able to isolate nonsymmetric triaryl-
methanes using THF contrary to toluene as a solvent (Table
2). Triarylmethanes are prevalent molecular frameworks in
material science, organic chemistry, and medicinal chemistry.11
These scaffolds are often encountered in natural compounds
and biologically active synthetic products. Thus, we decided to
explore the synthesis of nonsymmetric triarylmethanes 14a−n.
Aldehydes bearing alkyl and aryl substitution, cyclic and
polycyclic, and electron-rich heteroaromatics underwent 1:2
condensation reactions smoothly to give desired products
14a−n in moderate to good yields.
To confirm the mechanistic pathway for the synthesis of
furo[3,2,-c]coumarin via nonsymmetric triarylmethanes, a
couple of controlled experiments were performed (Scheme
Several Brønsted and Lewis acids were used to study the
transformation. Among them, a metal triflate catalyst Sc(OTf)3
B
Org. Lett. XXXX, XXX, XXX−XXX
Girmachew, Selamawit
