A concise synthesis of substituted benzoates

Cycloaromatization, via tandem cycloaddition – extrusion of carbon dioxide, between methyl isodehydroacetate or methyl coumalate and a variety of alkyne dienophiles has been investigated. This method provides an efficient synthesis of methyl 4-hydroxymethyl-2,6-dimethylbenzoate ( 1 ), a key intermediate in the preparation of retinal-based molecular probes.


Introduction
The Diels-Alder chemistry of bromo-2-pyrones has been studied in detail. 1 The cycloaddition of the related coumalate esters is a process that has been underutilized in organic synthesis and methodology. 2The reactions of coumalates with olefins typically follow an inverse-electrondemand motif. 2 Substituted coumalates have been used in total synthesis in two principal ways: cycloaddition with an electron-rich olefin to install a bicyclic lactone 3 and for cycloaromatization. 4he synthesis of a retinal-based biological probe (2) from mesityl aldehyde has been described (Figure 1). 5 A key intermediate in that synthesis was methyl 4-hydroxymethyl-2,6dimethylbenzoate (1), the preparation of which required three steps (one using carbon tetrachloride as the solvent) and provided 12% overall yield.We are interested in the preparation of similar photoaffinity analogues and consequently sought a more efficient preparation of 1.The cycloaromatization of a substituted coumalate could be such an alternative.The reaction of α-pyrones with alkynes yields aryl derivatives upon extrusion of carbon dioxide (Figure 2). 6The most typical alkyne reactive partners are phenylacetylene, a propiolate, or dimethyl acetylenedicarboxylate, which suggests that the electronic requirements of the cycloaddition can follow the usual motif.However, it is also important to note that the electronrich alkyne N,N-diethyl-1-propyn-1-amine has a greater reactivity with some pyrone derivatives than any of the aforementioned dienophiles.The preparation of 1 via such a cycloaromatization route would require the use of propargyl alcohol or its derivatives, thereby altering the electron demand from that observed in most cases.The work described herein is aimed at developing a more efficient synthesis of 1 via this cycloaromatization route.

Results and Discussion
Cycloaddition between methyl coumalate and propargyl alcohol is a reasonably facile process, which provides methyl 4-(hydroxymethyl)benzoate in good yield after 2 hours of heating in a sealed tube (Scheme 1).The oxabicyclo species is the presumed intermediate.It has not been directly observed in the course of this particular transformation, likely due to the facile loss of carbon dioxide; however, similar bicyclic lactones have been observed in related cycloadditions where the loss of CO 2 is not as favorable.

Scheme 1
The use of methyl isodehydroacetate as a starting material to generate the target compound (1) proves to be challenging.Methyl isodehydroacetate and propargyl alcohol also undergo cycloaddition with tandem extrusion of carbon dioxide to yield the expected trisubstituted benzoate (Scheme 1); however, much longer reaction times are necessary.
Envisioning the cycloaddition as an inverse-electron-demand Diels-Alder reaction 2 led to the investigation of Lewis acid catalysts, which could potentially facilitate the reaction by lowering the energy of the diene LUMO through hydrogen bonding interactions with the pyrone.However, propargyl alcohol, rather than methyl isodehydroacetate, appeared to be the optimal Lewis basic partner in this reaction, and in fact, treatment of the mixture with the broad array of Lewis acids enumerated below led only to decomposition or drastically reduced yields suggesting that hydrogen bonding with the dienophile was widening the HOMO-LUMO energy gap.
Propargyl acetate and TBS-protected propargyl alcohol also serve as viable dienophiles, providing the orthogonally protected trisubstituted benzoates 5 and 7.It was expected that protection of the hydroxyl group during the cycloaddition would enable the use of Lewis acid catalysis to facilitate the reaction.A variety of Lewis acids were screened for catalytic activity.Sc(OTf) 3 9 and SnCl 4 led to decomposition, while acetic acid, 10 trifluoroacetic acid, 10 camphor sulfonic acid, 10 triphenylcarbenium tetrafluoroborate, methylrhenium trioxide, 11 oxazaborolidinium salts, 12 and Pd(II)-BINAP 13 all led to reduced yields.Racemic tartaric acid 10 did, however, provide some modest yield enhancements that were encouraging.On the basis of these results, a few α-hydroxyacids (citric 10 and lactic acid) and dicarboxylic acids (succinic and 2,3-dimethylsuccinic acid) were further examined for catalytic potential.
Of these, citric acid was the most promising.The addition of a half equivalent of citric acid led to nearly double the amount of methyl 4-acetoxymethyl-2,6-dimethylbenzoate after 4 hours of heating (Table 1).However, the rate enhancement does diminish with extended reaction time, since 10 hours of heating with the same amount of catalyst led to only 78% product, as compared with the 58% observed in the absence of citric acid.A potential explanation for the efficacy of citric acid is that it appears to favor a conformation that would make 7-membered cyclic hydrogen bonding with the pyrone carbonyl feasible (Figure 3).With a method to obtain reasonable yields in a moderate length of time, the reaction was extended to several substrates.A summary of the results is presented in Table 2.The cycloadditions of methyl coumalate and methyl isodehydroacetate with propargyl alcohol (entries 1 and differ greatly in rate implying that the electron-poor diene and electronrich dienophile are well matched in the first case but not in the latter.The fact that addition of methyl groups on the diene diminishes the rate suggests that these cycloadditions follow the inverse-electron-demand paradigm (steric considerations are addressed below).Enhanced regioselectivity is obtained with methyl isodehydroacetate, potentially due to a combination of steric and electronic factors.

Table 2. Cycloaromatization reactions
Similar differences in regioselectivity are observed with propargyl acetate (entries 3 and 4) and TBS-protected propargyl alcohol (entries 5 and 6).Furthermore, the rate-enhancing effect of citric acid appears to be limited to the reaction producing 5 (entry 4).This may be due to the inverse-electron-demand.The hydrogen bonding illustrated in Figure 3 would render methyl isodehydroacetate slightly more electron poor, thereby facilitating the reaction.While this should also be true for the reaction of methyl isodehydroacetate with TBS-protected propargyl alcohol, the TBS group may lead to steric crowding, thereby negating the benefit of citric acid.
The use of dimethyl acetylenedicarboxylate as a dienophile leads to rapid reaction with both dienes (entries 7 and 8), which appears to indicate that the steric differences between the dienes need not have a pronounced effect on this reaction and that the traditional electron demand is at play in these cases.However, relatively sharp differences in reactivity are observed with the usage of less electron poor alkynes (entries 9 -12).Notably, the extremely sluggish reaction between methyl isodehydroacetate and ethyl 2-butynoate (entry 12) reveals that the reactants are poorly matched.Several of these latter reactions exhibited poor regioselectivity as well.
It is noteworthy that our observations regarding the reactions that produce 10a / 10b (entry 9) and 11a / 11b (entry 10) differ from those reported previously for an extremely similar system.6c Using methyl coumalate with methyl propiolate in one instance and ethyl isodehydroacetate with methyl propiolate in another, Effenberger and Ziegler reported the opposite regioselectivity.6c It is possible that subtle substituent effects account for our differing observations; however, the regioselectivity reported herein appears to be in accord with the results expected based on the complementary polarity of the reactants (Scheme 2).

Conclusions
Cycloaromatization of methyl isodehydroacetate and propargyl alcohol can be used to produce methyl 4-hydroxymethyl-2,6-dimethylbenzoate (1) in moderate yield and a single synthetic step.This represents a two-step reduction and a five-fold improvement in yield relative to the previously published method and should therefore facilitate the pursuit of retinal-based molecular probes.
The slow reaction of methyl isodehydroacetate with propargyl alcohol (and its derivatives), as well as the facile reaction with dimethyl acetylenedicarboxylate, suggests that this diene performs better in the traditional electron demand paradigm.This is further supported by the progressively slower reactions observed with dienophiles having less pronounced electron deficiency, such as ethyl propiolate and ethyl 2-butynoate.Steric factors appear to be of lesser importance as evidenced by the significant reduction in rate observed with ethyl propiolate (relative to dimethyl acetylenedicarboxylate) as a dienophile.
Methyl coumalate, on the other hand, acts efficiently as an ambiphilic diene as illustrated by its relatively facile reaction with all of the dienophiles examined.Steric factors alone appear not to account for the observed differences in reactivity between methyl isodehydroacetate and methyl coumalate based on the rapid reaction of both dienes with dimethyl acetylenedicarboxylate.

Experimental Section
General Procedures.Reagents were obtained from Aldrich and were used without further purification.Sealed tube reactions were conducted in Ace pressure tubes (#15, type A bushing).Flash column chromatography was performed using Aldrich silica gel 60 (70-230 mesh).Melting points were determined using a Mel-Temp II apparatus and are uncorrected.NMR spectra were collected on an Oxford AS400.Infrared spectra were obtained on a Mattson Instruments 4020 Galaxy Series spectrometer.GC/MS analysis was performed on a HP G1800C GCD Series II instrument.The column used was HP-5MS (Crosslinked 5% PH ME Siloxane), 30 m x 0.25 mm x 0.25 µm film thickness.The initial temperature was set at 150 °C, and the temperature was increased to 250 °C at a rate of 50 °C per min.Split injections of 2 µL were used with a flow rate of 2.0 mL/min.The inlet and detector were both maintained at 280 °C.

Figure 3 .
Figure 3. Possible hydrogen-bonding interaction between citric acid and the diene.

Table 1 .
Effect of citric acid on the cycloaromatization reaction a Conditions: (A) 180 °C, sealed tube; (B) 0.5 equ citric acid, 180 °C, sealed tube.b Yields are measured by GC/MS analysis of the reaction mixture.