Et 3 N-promoted sequential reactions for the synthesis of 6 H -benzo[ c ]chromenes

An interesting Et 3 N-promoted sequential reaction consisting of propargyl-allenyl isomerizations, intramolecular [4+2] cycloaddition and aromatization has been developed, providing a facile method for synthesis of 6 H -benzo[ c ]chromenes under mild conditions in moderate yields.


Introduction
6H-Benzo[c]chromenes are an important class of heterocycles due to their applications as bioactive compounds 1 and photoswitches in photochemical reactions. 2Previous reports for the synthesis of 6H-benzo[c]chromenes are few, and these approaches usually present some limitations in terms of regioselectivity, need for forcing reaction conditions or complex starting materials. 3Therefore, development of a synthetically useful methodology for 6H-benzo[c]chromenes using acyclic readily available starting materials attracted our attention and interest.

Scheme 1
In the reaction shown in Scheme 1, a conjugated enyne with an electron-withdrawing group was used as an efficient diene in an intramolecular [4+2] cycloaddition through propargyl-allenyl isomerization.We proposed that this kind of conjugated enyne might be used as an efficient synthon in the construction of 6H-benzo[c]chromenes. Retrosynthetically, 6H-benzo[c]chromenes could be prepared by intramolecular [4+2] cycloaddition and aromatization of conjugated enynes which in turn could be obtained conveniently by a Sonogashira coupling between alkynes and vinyl iodides (Figure 1).

Figure 1
According to the above synthetic route, herein we wish to report an efficient synthesis of 6H-benzo[c]chromenes from acyclic enyne substrates in moderate yields.

Results and Discussion
Synthesis of enynes.The synthetic route to conjugated enynes 5 is outlined in Scheme 2. Compounds 3 were synthesized from 2-(alkynyl)phenols 5 and 3-bromoprop-1-yne 2 in acetone using K2CO3 as the base.Conjugated enynes 5 were conveniently obtained by a Sonogashira coupling between alkynes 3 and vinyl iodides 4. 6

Scheme 2
Effect of base and solvent.In order to find the most efficient reaction conditions, we initially examined the cyclization reaction of 5a usiong various bases and solvents and the results are summarized in Table 1. a The reaction was carried out using 5a (0.18 mmol) in 1.5 mL of solvent and 0.5 mL of base.b Isolated yields.c Reactions were carried out at rt. d No product was obtained.
In an initial experiment, we observed the formation of 6H-benzo[c]chromene 6a when the reaction was performed in DMSO using Et3N as the base (Table 1, entry 1).Further screening revealed that strong organic inorganic bases were not suitable for the transformation (Table 1, entries 2-5).Next, we examined the effect of solvent on this reaction (Table 1, entries 6-13).A better yield was obtained when EtOH was used as the solvent.The reaction seem to give much more competitive yields with shorter reaction time when protic solvents were used (entries 10, 12-13 Table 1).

Cyclization of enynes 5 to 6H-benzo[c]chromenes 6.
With the optimized reaction conditions in hand (Table 1, entry 10), the scope and the limitations were examined (Table 2).From the results in Table 2, it is evident that the reaction proceeded smoothly to afford 6H-benzo[c]chromenes in moderate yields when R 1 was an alkyl or an aryl group (Table 2, entries 1-10). 7

Conclusions
In summary, we have developed an efficient method for the synthesis of 6H-benzo[c]chromenes in moderate yields under mild conditions using acyclic substrate.These 6H-benzo[c]chromenes bearing carbonyl functional groups may be converted to other interesting and useful structural units in organic synthesis.Further studies into the scope and synthetic applications of this transformation are being carried out in our laboratory.

Experimental Section
General.All 1 H-and 13 C-NMR spectra were measured in CDCl3 and recorded on a Brucker Avance III 500 MHz (125 MHz) spectrometer with TMS as the internal standard.Chemical shifts are expressed in ppm and J values are given in Hz.IR spectra were run on a Thermo Nicolet 6700 spectrometer.EIMS were determined with a Thermo ITQ 1100 mass spectrometer.HRMS were performed on a Waters GCT Premier instrument.Melting points were measured using CRC-1 melting point instrument and are uncorrected.Solvents were distilled before use.

Table 1 .
Optimization of reaction conditions for the cyclization of 5a a