A novel synthesis of polysubstituted phenols using the S n Ar reaction of 2,5-dinitrofuran

2,5-Dinitrofuran is readily available from 2-nitrofuran by treatment with concentrated nitric acid. The reaction of this compound with various nucleophilic reagents proceeds by an addition/elimination sequence (S N Ar) to furnish substituted 5-nitrofurans in good yield. Diels— Alder cycloaddition of the resulting activated furans with various π -systems affords transient [4+2]-cycloadducts that undergo nitro group elimination and subsequent aromatization to produce polysubstituted phenols.


Introduction
Nucleophilic substitutions using benzenoid aromatics have been proposed to proceed through an addition-elimination mechanism (S N Ar).This proposal is consistent with the available kinetic data. 1,2Molecular orbital calculations have been performed on the suspected intermediate Meisenheimer complex, 3 theories have been advanced to explain attack-site preferences, 4 and some theoretical work using bond energies have been carried out. 5In contrast to this situation, nucleophilic aromatic substitution on the furan ring has been little studied.Monographs dealing with the chemistry of furans either ignore the subject entirely or sometimes present just a few instances of this reaction. 6One of the reasons for this state of affairs is no doubt the fact that furan derivatives with substituents suitable for nucleophilic displacement are not that easily available.A substrate of some interest to our research program is 2,5-dinitrofuran 1 which is readily available from 2-nitrofuran by treatment with concentrated nitric acid. 7A survey of the literature revealed a limited number of examples where this diactivated furan underwent nucleophilic substitution. 8or the past several years, our laboratory has been interested in the Diels-Alder reaction of 2-substituted furans 9 as a method for preparing polyaromatic ring systems since these compounds are of interest as pharmaceutical agents. 10Our long-range goal in this area involves the use of 2nitro substituted furans such as 2 that contain both a suitable leaving group (i.e., SPh, OMe, NO 2 , etc.) and an olefinic tether which allows for an intramolecular Diels-Alder reaction (Scheme 1).The resultant cycloadduct 3 was expected to readily undergo ring opening and ejection of the leaving group to give phenols of type 4. With this goal in mind, model studies were undertaken to determine the facility with which 2,5-dinitrofuran 1 would undergo substitution with various nucleophiles.Our intention was to use the resulting products as substrates for Diels-Alder cycloadditions.The present paper documents the results of these studies.

Results and Discussion
Our initial endeavors focused on the reaction of 2,5-dinitrofuran 1 with soft carbon nucleophiles such as the anions derived from ethyl acetoacetate or dimethyl malonate.Indeed, this reaction proceeded smoothly and afforded the substituted nitrofurans 6 and 7 in 90% and 97% yield, respectively.These substitutions presumably proceed by the addition/elimination mechanism via the Meisenheimer intermediate 5 as shown in Scheme 2.

Scheme 2
To further illustrate the scope and synthetic utility of this S N Ar substitution reaction, we set out to expand the process using other nucleophilic agents.We found that treating dinitrofuran 1 with thiophenol in the presence of sodium hydride afforded 2-nitro-5-(phenylsulfanyl)furan 8 in 91% yield.Interestingly, the reaction of thioacetamide with furan 1 in the presence of NaH produced bis-(5-nitrofuranyl)-sulfide 11 as the exclusive product in 85% isolated yield (Scheme 3).The formation of 11 most probably proceeds through a sequence initiated by an addition-elimination of thioacetamide on the more nucleophilic sulfur atom to first produce 9 as a transient intermediate.Further reaction of 9 with NaH results in the loss of acetonitrile and the generation of thiolate 10 which reacts further with excess dinitrofuran to eventually produce sulfide 11.

Scheme 3
We also examined the S N Ar reaction of dinitrofuran with sodium ptoluenesulfinate.Displacement of one of the nitro groups with the sulfinate salt proceeded uneventfully to furnish sulfone 12 in 75% yield (Scheme 4).Exposure of 12 to hydrogen in the presence of Lindlar's catalyst did not produce the expected 2-amino substituted furan 13, but rather gave the imine tautomer 14 in 91% yield.This transformation is not at all unreasonable given the fact that the related 2-hydroxy-furan system is known to exist preferentially in the butenolide tautomeric form. 6

Scheme 4
Our attention was next directed toward the reaction of 2,5-dinitrofuran 1 with various oxygen and nitrogen nucleophiles.Treatment of a sample of 1 with both 4-pentyn-1-ol and 4-penten-1-ol in the presence of NaH furnished the expected 2-alkoxy-5-nitro substituted furans 15 and 16 in 53% and 61% yield, respectively (Scheme 5).Thermolysis of 15 at 120 °C failed to produce any characterizable products and only recovered starting material was obtained.

Scheme 5
On the other hand, heating a sample of 16 at 120 °C afforded a 2:1-mixture of chromanols 17 and 18 in 50% overall yield.The major chromanol (i.e., 17) produced in this reaction can be attributed to the formation of a Diels-Alder adduct (i.e., 19) derived from cycloaddition of the dienic system of the furan across the tethered π-bond.Opening of the oxabridge is assisted by the lone pair of electrons on the neighboring oxygen atom.1,2-Migration of the nitro group to the adjacent double bond of the incipient oxonium ion then takes place to give enone 20 (Scheme 6).This transient intermediate is converted to nitro-chromanol 17 by subsequent tautomerization and air oxidation.Formation of the minor product 18 may be rationalized by invoking a competitive sequence involving loss of HNO2 to give dienone 21 followed by a 1,3-sigmatropic hydrogen shift to ultimately produce chromanol 18.After some experimentation, we eventually found a set of conditions that suppressed nitro group migration.The best conditions for minimizing formation of nitrochromanol 17 consisted of performing the thermolysis of 16 in tbutanol at 120 °C in the presence of potassium carbonate.These conditions resulted in the isolation of chromanol 18 as the exclusive product in 54% yield.

Scheme 6
The reaction of 2,5-dinitrofuran 1 with a typical secondary amine such as morpholine in ether at 35 0 C afforded the morphilino-substituted nitrofuran 22 in 97% yield.Heating a sample of 22 with phenyl vinyl sulfone (120 °C, 12 h) in the presence of K2CO3 gave phenol 23 in 40% yield which is seemingly derived from a [4+2]-cycloaddition followed by nitro group ejection and subsequent aromatization.
Using the S N Ar reaction of 2,5-dinitrofuran, we were also able to synthesize Ntosylamino furans 24 and 25 in 77% and 84% yields, respectively.Heating a sample of 24 in toluene at reflux resulted in a mixture of phenols 26 (50%) and 27 (14%).Similar results were obtained when the dienophile tether was lengthened by one methylene unit as illustrated in Scheme 7 for the conversion of nitrofuran 25 into 28 (55%) and 29 (7%).From these results it is evident that nitro-substituted aminofurans display some interesting cycloaddition chemistry.

Scheme 7
Two distinct reaction pathways are observed: (1) cycloaddition followed by loss of the nitro group to give phenols (i.e., 26 and 28) and ( 2) cycloaddition followed by 1,2-nitro migration to eventually afford the corresponding o-nitrophenols 27 and 29.Similar 1,2-shifts have been reported in cycloadditions involving silyl-substituted furans, 11 thereby providing good precedence for this rearrangement pathway.
In conclusion, this paper describes a versatile new approach to phenols with various substitution patterns.The synthetic procedure described here involves a S N Ar substitution reaction of 2,5-dinitrofuran with different nucleophilic reagents as a method for producing 5nitro substituted furans.A subsequent Diels-Alder cycloaddition of the activated furan with several alkenyl π-bonds furnishes transient [4+2]-cycloadducts that are readily converted to polysubstituted phenols.Further application of the method and its utilization for alkaloid synthesis are in progress and will be reported in due course.

4-(5-Nitro-furan-2-yl)morpholine (22).
To a solution containing 0.33 g (2.1 mmol) of 2,5dinitrofuran in 25 mL of ether was added 0.3 g (5 mmol) of morpholine.The solution was stirred at 35 °C for 2.5 h and was concentrated under reduced pressure.The residue was subjected to silica gel chromatography to give 0.