The use of Hagemann’s Esters to prepare highly functionalized phenols and benzenes §

Hagemann’s esters can be converted into highly functionalized phenols or arenes. The systematic functionalization of Hagemann’s ester derivatives permits the preparation of tri-and tetraalkyl-substituted phenols or tetra-, penta-, and hexaalkyl-substituted benzenes. Kotnis’s aromatization procedure was found to be solvent dependent, and Suzuki couplings were found to be sensitive to steric hindrance. Wittig olefination and ortho -Claisen reactions were reliable means to introduce alkyl substituents at C-4 and/or C-5 positions, respectively. The acid-promoted dehydration of tertiary alcohol 46 to produce enone 47 , followed by its selective alkylation (cf. 48 ) is new.


Introduction
Many naturally occurring and biologically active compounds contain a highly substituted benzene ring. 1 While functionalization of benzene has been an active area of organic chemistry for more than 150 years, the number of strategies for preparing highly alkylated phenols 2a-c and highly alkylated benzenes is limited.2d-f In 1894, Hagemann 3a treated two equivalents of ethyl acetoacetate 1 with one equivalent of diiodomethane and excess sodium methoxide to form glutamate diester 2; further treatment of 2 with base and heat produced cyclic ester 3 (Scheme 1).Although the initial structure of 3 required revision, 3b these cyclohexenone derivatives became known as "Hagemann's esters."One year after Hagemann's synthesis of 3, Knoevenagel improved its preparation by coupling 1 with formaldehyde to generate Michael acceptor 4 in situ, which reacts with a second molecule of 1 to yield diketone 2, 4 which in turn, undergoes intramolecular aldol reaction to produce cyclic alcohol 7. The mechanism of the formation of Hagemann's ester has been the subject of extensive investigation, 5 but it was not until 1984 when Hoye and co-workers established that aldol 7 forms lactone 8, which loses carbon dioxide to form ester 3. 6 Horning and co-workers developed conditions so that Knoevenagel's modification could be carried out in a single operation; 7 this one-pot, tandem Knoevenagel/intermolecular Michael addition/intramolecular aldol reaction/intramolecular trans-esterification/decarboxylation sequence represents one of the earliest cascade reactions. 8A useful modification of Knoevenagel's general procedure was to employ an aldehyde (or a ketone) in the condensation step, 9 which introduces one alkyl (or two alkyl) substituent(s) at the C-6 position (cf. 1  5  6  7  8  9).A comprehensive review of the synthetic utility and versatility of Hagemann's esters has recently been published. 10heme 1.The intermediates produced during a Hagemann's ester synthesis.
Hagemann's esters can undergo selective alkylation at three sites.In 1943, Smith and  Rouvault reported that 3 undergoes alkylation exclusively at C-3 (cf. 10, Scheme 2). 11Many syntheses have utilized this alkylation, followed by saponification and decarboxylation, to prepare 2-alkyl-3-methyl-2-cyclohexenones. 12Once the C-3 position of Hagemann's ester is substituted, Dyier and coworkers found that a second alkyl substituent can be introduced at C-1 in high yield (cf. 11). 13The introduction of an alkyl group at C-5 (cf.9) produces enone 12, which upon saponification and decarboxylation of the C-1 ester produces enone 13 having four different alkyl substituents.Substituted cyclohexenones are easily aromatized using palladium catalyzed dehydrogenation 14 or by introducing a leaving group at C-5 followed by elimination and keto-enol tautomerization. 15If an alkyl group is introduced at C-6 while preparing the Hagemann's ester, the systematic introduction of alkyl substituents at C-1, C-3, and C-5 produces phenols with five different alkyl substituents (cf.15).A structural feature common to all Hagemann's esters is the methyl group at C-2.A project in our labs required the preparation We believed that the use of t-butyl alcohol in the aromatization procedure would produce only p-hydroxybenzoate 16 because t-butyl alcohol is less likely to act like methanol.The treatment of Hagemann's ester 18, readily prepared by the procedure developed by McCurry and Singh, 9c with two equivalents of iodine in refluxing t-butyl alcohol gave p-hydroxybenzoate 19 in 60% yield (Scheme 4).The alkylation of Hagemann's esters 18 and 22 with methyl iodide produced esters 20 and 23, respectively.Ester 20 was aromatized in 65% yield using iodine in refluxing t-butyl alcohol, but aromatization of 23 was slower and occurred in only a 34% yield.Scheme 4. Our modification of Kotnis's aromatization procedure.
The alkylation of an alkyl substituent at C-5 of a Hagemann ester is problematic. 10However, an allyl group can be easily introduced at the C-5 position of the appropriate phenol via an ortho-Claisen rearrangement. 17For example, phenols 21 and 24 were converted smoothly into their allyl ethers 25 and 27, respectively, which were heated in diethylaniline to give phenols 26 and 28, respectively, in good yields (Scheme 5).This strategy allows to construct a fully functionalized phenol in a few steps with complete control of the substituents on the phenyl ring: (1) the C-2 methyl was installed during the synthesis of the Hagemann's ester; (2) the C-6 alkyl substituent was governed by the choice of aldehyde used in the ester synthesis; (3) the substituent at C-3 was dictated by the choice of the alkylating agent; and (4) even though the o-Claisen rearrangement introduces an allyl group at C-5, the double bond can be isomerized to the styrenyl position and then oxidized to generate either an aldehyde or a carboxylic acid.Since many synthetic targets may not require alkyl substituents at every position of an arene, a route for preparing phenols without the ester moiety at the C-1 position was studied.The ester moiety present in 18 and 20 is vinylogous to the enone and can undergo decarboxylation using the same conditions that apply to -keto esters (Scheme 6).Accordingly, heating esters 18 and 20 to 145 °C in moist DMSO containing LiCl gave enones 29 and 31 in good yields.Refluxing enone 29 or 31 in ethylene glycol in the presence of 10% Pd/C (Horning's aromatization conditions 14 ) produced phenols 30 or 32, respectively.Scheme 6. Preparation of trisubstituted phenols.
Our efforts then turned toward the synthesis of 4-alkyl-substituted benzenes.In the Suzuki coupling reaction alkylboron reagents can be cross-coupled with aryl or vinyl halides 18a and triflates 18b by using a Pd catalyst.The application of this method to our substrates would allow for highly alkylated phenols to be converted into more functionalized arenes.For example, phenol 21 was converted into triflate 33 using pyridine and triflic anhydride (Scheme 7).Triflate 33 and the alkylborane formed by reacting 9-BBN with 1-octene were treated with Pd(PPh3)4, to produce arene 34 in 57% yield.Triflate 35 was generated from phenol 32 in 86% yield.Standard Suzuki coupling conditions gave benzene derivative 36 in 82% yield.Scheme 7. Preparation of a tetra-or a pentasubstituted benzene.
Interestingly, an attempted Suzuki coupling of triflate 37 failed (Scheme 8), which suggests that substitution at the positions ortho to the triflate generates steric crowding that complicate the Suzuki coupling reaction.A search of the literature failed to find examples of successful Suzuki couplings between an aryl triflate with two ortho substituents under standard Suzuki conditions.Scheme 8. Failure of the Suzuki coupling with sterically crowded triflates.
Traditional methods to functionalize the C-4 position were also investigated.For example, treatment of enone 29 and 31 with 1.3 equivalents of n-butyllithium gave tertiary alcohols 38 and 41, respectively (Scheme 9).Both alcohols rapidly dehydrated to produce methylenecyclohexenes.The formation of the exocyclic double bond was inconsequential as dienes 39 and 42 aromatized in good yield affording the polyalkyl-substituted benzenes 40 and 43, respectively.Scheme 9. Preparation of tetrasubstituted alkylbenzenes.
Methylenecyclohexenes similar to 39 and 42 can also be prepared by treating a substituted 2cyclohexenone with a Wittig reagent.For example, treatment of enone 29 with methylene triphenylphosphonium ylide produced a mixture of methylenecyclohexene 44 and cyclohexa-1,3diene 45, which produced mesitylene in 76% yield upon treatment with palladium (Scheme 10).In contrast to the normal one-pot Hagemann's ester synthesis, careful monitoring of the reaction allowed us to stop the cascade of transformations at the tertiary alcohol 46.Treating 46 with p-TsOH produced enone 47, which retains the C-5 ester.Although both the C-1 and C-5 methine positions are doubly activated, we predicted that the more accessible H-5 would be abstracted preferentially to form the C-4, C-5 enolate.When enone 47 was treated with sodium hydride and methyl iodide, only diester 48 was isolated (Scheme 11).In order to prove this structure, diester 48 was saponified and decarboxylated to give 3,5,6-trimethyl-2-cyclohexenone 49, which was then aromatized to produce phenol 32, which was synthesized earlier through a different route.
Scheme 14 shows how hexamethylbenzene 60 could be synthesized based on the findings reported in this paper.The synthesis of whimsical hexasubstituted benzenes, such as 61, can be envisioned using this methodology.Scheme 14.The preparation of hexamethylbenzene.
In summary, we have shown that Hagemann's esters can be used to prepare polysubstituted phenols and benzene derivatives in a concise, completely regioselective fashion.In addition, we observed that although Suzuki coupling reactions can be used to convert complex phenols into complex benzene derivatives, triflates with two ortho substituents failed to couple.A substituent can be readily introduced at C-4 by using standard organometallic additions or Wittig reactions.

Experimental Section
General.Routine 1 H NMR spectra were determined in CDCl3 on either a Bruker AC250 instrument ( 1 H: 250 MHz; 13 C: 62.9 MHz) or a Bruker AC300 instrument ( 1 H: 300 MHz; 13 C: 75.5 MHz).Chemical shifts are reported relative to TMS.The data reported as integer numbers are accurate to within ±10%.Genuine effort was made to ensure that NMR spectra did not contain any solvent "impurities."All samples were "pure" by 1 H and 13 C NMR analysis.Infrared (IR) spectra were recorded as thin films between polished sodium chloride plates on a Perkin-Elmer FT-IR 1600.Electron impact mass spectra (EIMS) were recorded on a Finnigan 4000 spectrometer (70 eV) and are expressed in m/z units.Anhydrous THF and diethyl ether were prepared by refluxing with, and distillation from sodium/benzophenone under a nitrogen atmosphere in a recycling still.Anhydrous DMF was prepared by refluxing over, and distillation from calcium hydride.All reactions were run under nitrogen using standard laboratory techniques for the exclusion of oxygen and moisture and were monitored by TLC analysis until the starting material was completely consumed.CAS numbers were provided for only a few compounds.

General procedure A. Alkylation of Hagemann's esters
NaH (1.1 molar equiv relative to the ester) was degreased with hexanes and the residual solvent was removed by vacuum.NaH was placed under nitrogen and cooled to -15 °C.Dry THF (10 mL) was added to the NaH.The Hagemann's ester (1.0 eq) in THF (25 mL) was added slowly to the stirred NaH, after which the mixture was stirred at -15 °C for 1 h.An alkyl halide (1.5 equiv) was then added and the reaction mixture was warmed to room temperature and stirred overnight.The reaction mixture was diluted with ether to four times the original volume.The organic layer was washed with water (4 x 25 mL).The aqueous phase was extracted with ether (3 x 10 mL).The organic extracts were combined, washed with brine, dried over anhydrous MgSO4, filtered, and then concentrated.The product was isolated by flash chromatography on silica gel. 20

General procedure B. Aromatization of alkylated Hagemann's esters
The C-3-alkylated Hagemann ester (cf.10) (1 eq) was dissolved in t-butyl alcohol (150 mL).Iodine (2 equiv) was added portionwise.The reaction mixture was refluxed, while maintaining the solvent level between 125 mL and 150 mL.The reaction mixture was cooled and the solvent was removed by rotary evaporation.The resulting residue was taken up in ether (200 mL) and washed with water (20 mL), and 10% sodium thiosulfate (3 x 20 mL).The ether layer was concentrated to one-third its original volume and was then extracted with 4% NaOH(aq) (4 x 15 mL).The basic extract was then cooled to 0 °C using an ice bath and was acidified with 10% HCl(aq).The acidified layer was then extracted with ether/ethyl acetate 1:1 (3 x 40 mL).The organic extracts were combined, washed with brine, dried over anhydrous MgSO4, filtered, and then concentrated.

General procedure C. Synthesis of allyl aryl ethers
The phenol 21 (1.0 equiv) was dissolved in dry DMF (18 mL).Allyl chloride (1.4 equiv), potassium carbonate (2 equiv), and potassium iodide (catalytic amount) were added sequentially and the reaction mixture was stirred for 24 h.The reaction mixture was diluted with ether (125 mL) and washed with water (3 x 30 mL).The aqueous phase was extracted with ether (20 mL), and the ethereal extracts were combined, washed with 10% aqueous cupric sulfate (20 mL) and brine (10 mL).The organic layer was dried over anhydrous MgSO4, filtered, and then concentrated.The Claisen rearrangement precursor was isolated using flash chromatography on silica gel.

General procedure D. ortho-Claisen rearrangement
The allyl aryl ether (1.0 equiv) was dissolved in 2 mL of N,N-diethylaniline.The reaction mixture was sealed in a thick-walled glass tube equipped with a Teflon screw top (Ace Glass) and was heated at 200 °C for 12 h.The reaction mixture was cooled and diluted with ether to ten times its original volume.The organic phase was washed with cold 5% HCl(aq) (4 x 5 mL), and brine (5 mL).The organic phase was dried over anhydrous MgSO4, filtered, and then concentrated.The rearrangement product was isolated by flash chromatography on silica gel.

General procedure E. Synthesis of triflates
The phenol (1.0 equiv) was dissolved in pyridine (0.4 mL).The reaction mixture was cooled to 0 °C.Triflic anhydride (1.1 equiv) was added dropwise, and the reaction mixture was stirred at room temperature for 20 h.The reaction mixture was poured into water (2 mL) and ether (25 mL) was added.The organic layer was washed with water (3 x 3 mL) and brine (3 mL), and dried over anhydrous MgSO4, filtered, and then concentrated.The crude triflate was isolated via flash chromatography on silica gel.

General procedure F. Suzuki coupling of triflates
To a flask at 0 °C was added 9-BBN (0.5 M solution in THF, 1.1 mmol) and 1-octene (1.1 mmol).The mixture was warmed to room temperature and stirred at room temperature for 3 h.Dioxane (5 mL), K3PO4 (1.5 mmol), Pd(PPh3)4 (0.025 mmol), and triflate (1.0 mmol) were added and the resulting mixture was heated at 85 °C for 5 h.The residual boron reagent was oxidized with 3 M NaOAc(aq) (0.5 mL) and 30% H2O2 at room temperature for 1 h.The reaction mixture was poured into water (5 mL) and diluted with ether (40 mL).The organic layer was washed with water (3 x 3 mL) and brine (3 mL).The organic layer was dried over anhydrous MgSO4, filtered, and then concentrated.The coupled aromatic product was purified via flash chromatography on silica gel.

General procedure G. Aromatization of 2-cyclohexen-1-ones
To a solution of an alkylated 2-cyclohexen-1-one (1.0 equiv) in ethylene glycol (6.0 mL) at room temperature was added 10% Pd/C (100 mg / 1 g of enone).The solution was refluxed for 6 h.The solution was cooled to 50 °C and filtered to remove the catalyst, which was washed with hot ethyl acetate (3 x 15 mL).The organic phases were combined, washed with water (6 x 10 mL) and then concentrated at reduced pressure.The residue was taken up in ether (10 mL) and extracted with 5% NaOH(aq) (3 x 5 mL).The basic extracts were combined, cooled in an ice bath, and then acidified with 10% HCl(aq).The aqueous phase was extracted (3 x 15 mL) with ether/ethyl acetate 1:1.The organic phases were combined, washed with brine, dried over anhydrous MgSO4, filtered, and concentrated.

General procedure H. Decarboxylation of methyl 4-oxo-2-cyclohexenecarboxylates
The substrate (1.0 equiv) was dissolved in DMSO (3.0 mL).Water (2 mL) and LiCl (2 equiv) were added.The reaction mixture was heated at 145 °C on an oil bath for 6 h, and was cooled to room temperature and diluted with ether (10 mL).The organic layer was washed with water (6 x 3 mL) and brine (3 mL), dried over anhydrous MgSO4, filtered, and then concentrated.The resulting 2-cyclohexenone was purified via flash chromatography.

General procedure I. Decarboxylation of Hagemann diesters
Into a round bottom flask was placed EtOH (4 mL), water (1 mL), and KOH (7 equiv).The diester (1.0 equiv) was dissolved in EtOH (5 mL) and added dropwise to the stirred KOH solution.The reaction mixture was refluxed under nitrogen for 12 h.After cooling, the solution was diluted with water (10 mL) and then concentrated using a rotary evaporator to remove the ethanol.The reaction mixture was acidified with 6 M HCl to pH 2 and refluxed for 2 h.After cooling to room temperature, the reaction mixture was extracted with ether (3 x 10 mL).The organic layer was washed with water (5 mL), and brine (5 mL).The organic layer was dried over anhydrous MgSO4, filtered, and then concentrated.The product was purified by chromatography on silica gel.

General procedure J. 1,2-Addition of an organolithium reagent to 2-cyclohexenones
Ether (5 mL) was added to a round bottom flask.n-BuLi (2.5 M solution in hexanes, 9.05 mmol, 1.25 equiv) was added and the solution was cooled to -78 °C.The substrate (6.96mmol, 1.0 equiv) dissolved in ether (5 mL) was added dropwise and the resulting reaction mixture was stirred at room temperature for 4 h.The reaction mixture was poured into cold saturated NH4Cl(aq) (20 mL) and extracted with ether (3 x 15 mL).The organic layer was washed with water (5 mL) and brine (5 mL).The organic layer was dried over anhydrous MgSO4, filtered, and concentrated.

General procedure K. Dehydration of tertiary alcohols
The allylic alcohol (1.14 mmol) was dissolved in DCM (2 mL).The resulting solution was cooled to 0 °C.To the stirred solution was added p-TsOH (0.3 mmol).The reaction mixture was warmed to room temperature and stirred overnight.The reaction mixture was diluted with DCM (10 mL) and washed with saturated NaHCO3(aq) solution (2 x 3 mL).The organic layer was dried over anhydrous MgSO4, filtered, and then concentrated.The resulting diene was isolated via chromatography on silica gel.
Mesitylene.The mixture of 3-methylene-1-cyclohexene 44 and cyclohexa-1,3-diene 45 (127 mg, 1.04 mmol) was mixed with ethylene glycol (1 mL) and placed in a thick-walled glass tube equipped with a Teflon screw cap (Ace Glass).To this mixture was added 10% Pd/C catalyst (15 mg).The mixture was placed under nitrogen and the tube was sealed.The reaction mixture was heated at 190 °C for 4 h.After cooling to 50 °C, the reaction mixture was filtered to remove the catalyst, which was washed with hot ethyl acetate (3 x 3 mL).The organic phases were combined, washed with water (3 x 1.5 mL), and brine (1 mL).The organic phase was dried over anhydrous MgSO4, filtered, and then concentrated to furnish a crude oily residue (117 mg).