Intramolecular cycloaddition reaction of bromo and nitro substituted furanyl amides

The intramolecular Diels-Alder reaction (IMDAF) of an N -alkenyl substituted furanyl amide was investigated. Upon thermolysis at 80-110 o C, a smooth IMDAF reaction occurred to provide a stable aza-7-oxabicyclo[2.2.1]heptane cycloadduct in high yield. The intramolecular cyclization of the related 5-bromo substituted furanyl amide was found to proceed at a much faster rate and in higher yield than the unsubstituted variant. The rate enhancement observed by incorporating a bromine in the 5-position of the furan ring appears to be general. The origin of the increased rate of cycloaddition for the 5-bromo substituted furan when compared to the unsubstituted example can be attributed to an increase in reaction exothermicity; this both decreases the activation enthalpy, and increases the barrier to retrocycloaddition. Bromine substitution on furan also increases reactant energy and stabilizes the product due to the preference of the electronegative bromine atom to be attached to a more highly alkylated, and therefore more electropositive framework. An unusual isomerization-cyclization reaction of a 5-nitro substituted furanyl amide was also found to occur under microwave conditions and provided a 1,4-dihydro-2 H - benzo[4.5


Introduction
The rhodium(II)-catalyzed reaction of α-diazo ketones bearing tethered alkyne units represents a powerful method for the construction of a variety of polycyclic skeletons. 1Exposure of the starting α-diazo ketone to a rhodium(II) catalyst results in cyclization of the α-keto carbenoid to an intermediate in which carbene-like reactivity has been transferred to one of the original alkyne carbon atoms.A neighboring functional present on the backbone then traps the cyclized intermediate via known carbenoid chemistry to give various products. 2During the course of our studies in this area, we reported on a novel construction of bicyclic furans by coupling a metal carbenoid cyclization onto a tethered alkyne with an electrocyclization reaction (Scheme 1). 3 Transformations of this type are of considerable synthetic utility, since the vast majority of furano-sesquiterpenes are functionalized at the C 3 and C 4 position of the furan ring. 4,52][13][14][15][16][17] The utility of this cyclization approach to ring construction would be significantly expanded if the resulting bicyclic furan 2 was to undergo a subsequent [4+2]-cycloaddition, since a cyclohexane annulation would then result (i.e., 2→4→5).As part of our broader interest in using furan-cycloaddition products for the synthesis of natural products, 18,19 we examined the strategic incorporation of several functional groups into the furan moiety that could be leveraged for the further transformation.

Results and Discussion
Our initial studies focused on an intramolecular variation of the Rh(II)-catalyzed cyclization/Diels-Alder cycloaddition sequence of a propargyl diazo malonic ester system.The reaction of diazo ester 6 with Rh 2 (OAc) 4 followed by protiodesilylation with TBAF produced furan 7 in good yield.Heating a sample of 7 at 145 o C in xylene furnished indacene dione 10 (36%) and the dienol-substituted lactone 11 (63%) (Scheme 2).These products are presumably derived by an initial IMDAF reaction (intramolecular Diels-Alder of furan) 20 followed by opening of the oxybridge of cycloadduct 8 to give oxonium ion 9.A subsequent loss of a proton from either of the two available positions nicely accounts for the products formed.
In contrast to this result, thermolysis of the related bromofuran 13, derived from the Rh(II)catalyzed reaction of diazo ester 12, gave the unusual rearranged bromide 17 as the major product in 43% yield (Scheme 3).Presumably, 17 arises from an initial intramolecular Diels-Alder reaction of furan 13 to give oxabicycle 14.Fragmentation of the oxabridge results in a zwitterionic intermediate 15, which can ketonize with the expulsion of a bromide ion, producing oxonium ion 16.The ejected bromide ion then attacks the oxonium ion at the adjacent methylene position, leading to the observed product.

Scheme 3
Intrigued by these results and considering the importance of 7-oxabicyclo [2.2.1]heptanes as valuable synthetic intermediates, we decided to examine some related systems that could provide polyfunctional oxabicycles.5-Bromo-2-furoyl amide 19 was prepared by N-allylation of the secondary amide 18 under phase transfer conditions (Scheme 4).Heating a sample of furan 19 at 110 o C for 90 min provided the stable oxatricycle 20 as a single diastereomer.The stereochemistry of 20 is consistent with preferred exo-orientation of the tether in the Diels-Alder cycloaddition reaction and is analogous with that reported by others for related furanyl systems possessing short tethers. 21In marked contrast to this finding, it was necessary to heat the unsubstituted amidofuran (X = H) for one week at 110 o C in order to complete the cycloaddition of 22 to 23.The rate enhancement observed by incorporating a bromine or another halogen group at the 5-position appears to be general. 22The origin of the increased bimolecular cycloaddition rate for the 5-bromo-substituted furans was recently investigated by Houk and Pieniazek using quantum mechanical calculations. 23The origin of the increased rate of cycloaddition for the 5-bromo substituted furan when compared to the unsubstituted example can be attributed to an increase in reaction exothermicity; this both decreases the activation enthalpy, and increases the barrier to retrocycloaddition.Bromine substitution on furan also increases reactant energy and stabilizes the product due to the preference of the electronegative bromine atom to be attached to a more highly alkylated, and therefore more electropositive framework.
The remarkable enhancement in the rate of the cycloaddition involving bromo furans, combined with our recent success with cycloadditions across heteroaromatic π-systems, 24 also prompted us to examine the IMDAF reaction using the electron withdrawing nitro group, rather than the bromo-substituent.Accordingly, we prepared the 5-nitro-furan variant 24 and found that when nitrofuran 24 was exposed to microwave irradiation for 15 min in N-methyl-2pyrrolidinone (NMP), furan 25 was isolated as the major product (Scheme 5).Compound 25 was unequivocally assigned by a single crystal X-ray analysis (Figure 1).A more detailed study of the reaction showed that catalytic amounts of 2,6-lutidine enhanced the formation of 25, suggesting a mechanism involving a base catalyzed tautomerization of the furfuryl moiety to give intermediate 26 as a transient species.The lone pair of electrons on the amide nitrogen facilitates the loss of the nitro group to furnish acyl iminium ion 27 which then undergoes a subsequent cyclization with the adjacent benzofuran as shown in Scheme 6.

Scheme 6
In conclusion, the results presented herein demonstrate the versatility of the intramolecular [4+2]-cycloaddition reaction of substituted furans.Different rearrangement pathways of the resulting oxabicyclo adducts become available depending on the nature of the substituent group attached to the furan.We are currently investigating application of the methodology outlined here toward the synthesis of several alkaloid natural products.