Journal of Organic Chemistry, 2005 , vol. 70, # 11 p. 4338 - 4345

Improved Alkylation and Product Stability in Phosphotriester Formation through Quinone Methide Reactions with Dialkyl

Phosphates

Brian A.Bakke,Matthias C.McIntosh,and Kenneth D.Turnbull*

Department of Chemistry and Biochemistry,University of Arkansas,Fayetteville,Arkansas 72701

kturnbul@https://www.wendangku.net/doc/df18390864.html,

Received January 10,

2005

Investigating reactions of functionalized p-quinone methides continues to advance our design of a reagent being developed for controlled,in situ modification of DNA via phosphodiester alkylation.Previously reported investigations of p-quinone methides derived from catechols allowed for trapping of isolable trialkyl phosphates for characterization and mechanistic information.However,lactone formation with these derivatives required long reaction times,resulting in an unfavorable mixture of trialkyl phosphate and hydrolysis products.To enhance the rate and efficacy of trialkyl phosphate formation and trapping,a phenol derived p-quinone methide has been designed to enforce a conformation favoring lactonization of the dialkyl phosphate alkylated intermediate.The relative rates of phosphodiester alkylation and subsequent trapping of the phosphotriester adduct have been examined by UV and 1H NMR analysis for p-quinone methide precursor 1and the corresponding control,1′.The incorporation of a methyl group at the meta -position of 1(relative to 1′)significantly improves the rate of lactionization to provide a much higher yield of the desired product,lactonized phosphotriester 5.The control reaction with 1′afforded only a minor amount of the corresponding lactonized trialkyl phosphate 5′.

Introduction

The role of quinone methide intermediates in bio-reductive processes is well-established.1-5Investigations with DNA and nucleic acids have predominantly been carried out with o -quinone methides 6-12and less with p-quinone methides 13-15focusing on base alkylation.In developing a research program around the application

of quinone methides to drug design,drug delivery,and biomolecular labeling,we have investigated the reactivity and formation of a variety of p-quinone methides to optimize alkylation of mildly nucleophilic phospho-diesters as models for nucleic acid polymers.

We have shown that phosphodiester alkylation with a p-quinone methide is a second-order,reversible process

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https://www.wendangku.net/doc/df18390864.html,.Chem.2005,70,4338-434510.1021/jo050050s CCC:$30.25?2005American Chemical Society

Published on Web 04/20/2005

leading to the rapid,kinetic-favored formation of a phosphotriester followed by a very slow hydrolysis of that product to a benzyl alcohol.The quinone methide alkyl-ation of the phosphodiester is in competition with the significantly slower,thermodynamic-favored,direct hydro-lysis of the quinone methide to produce a benzyl alcohol.16 To maximize phosphotriester product formation,the incorporation of a trapping moiety to stabilize the product and prevent reversibility became necessary.We previ-

ously reported an approach to accomplish this with a catechol-derived quinone methide designed to alkylate a phosphodiester via a characterizable p-quinone methide followed by in situ lactonization.17Although the approach proved effective,affording the desired trialkyl phosphate product in good yield,the intramolecular trapping via lactonization proved to be a slow,temperature-dependent process requiring rigorously anhydrous conditions,and product isolation was challenging.

Conformationally enforced acceleration of lactoniz-ation reaction rates through steric effects is well-precedented.18-23Lactonization studies of a variety of hydrocoumarinic acids demonstrated that the relative rates increased substantially with increasing substituent bulk.The Borchardt laboratory has extensively examined24-35and reviewed36-38the use of coumarin-based,esterase-sensitive cyclic prodrugs incorporating the“trimethyl lock”concept elegantly utilized within a linker for the facile release of drugs in vivo.

Based on such steric effects for enhancing lactonization rates in related systems,we have redesigned the p-quinone methide derivative in an attempt to increase the rate of the lactonization reaction and afford a more stable phosphotriester product.However,as observed in our previous work,17lactoniozation rates that are too rapid can preclude the ability to form the quinone methide.Scheme1demonstrates the envisioned reaction of designed p-quinone methide2.Although the methyl propionate arm of1was designed for facile lactonization, it required sufficient stability to allow formation of p-quinone methide2without concomitant lactonization. It was necessary that p-quinone methide2maintain sufficient reactivity with the presence of the methyl substituent(R1)adjacent to the alkylidene reaction center in order to rapidly alkylate a dialkyl phosphate to afford 3.Alkylation to3was to be followed by lactonization through population of a reactive conformation enforced by steric interaction with the adjacent methyl group, leading to the desired stabilized trialkyl phosphate5.It was hoped that the lactonization of3might prove facile enough to allow the kinetic-favored product to be drained off through lactonization to afford5and preclude revers-ibility back to quinone methide2,where hydrolysis to the thermodynamic-favored4can undergo lactonization to afford6.It was further hoped that trialkyl phosphate 5might prove more stable than the corresponding trialkyl phosphates afforded in our previous work.17

To determine the effect of the methyl group on quinone methide formation from1,alkylation of quinone methide 2,and stereopopulation control in3,two functionalized quinone methide derivatives were desired for investiga-tion.The syntheses of1and the corresponding control without the methyl group,1′,were accomplished for this purpose(Figure1).

We report the results of our investigations,which demonstrate the effectiveness of incorporating a methyl substituent ortho to the propionic ester lactonizing functionality for enhanced lactonization and thereby stabilization of the kinetic-favored,phosphotriester prod-uct16derived from quinone methide alkylation of a phosphodiester.Notably,the incorporation of this pro-pionic ester and o-methyl substituent still allowed for quantitative formation of the desired p-quinone methide from the phenol and offered no impedance to the quinone methide alkylation reaction with the phosphodiester. Further,the methyl substituent afforded considerable improvements in the rate and temperature dependence of lactone formation.The overall design also contributed to a highly stable trialkyl phosphate product.

Results and Discussion

Synthesis of Quinone Methide Precursors.Our investigations required the synthesis of phenols1and

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85.F IGURE1.Quinone methide precursors1and1′.

Improved Phosphotriester Formation

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1′as precursors for the corresponding quinone methides 2and 2′.Phenols 1and 1′also incorporated a carbamate protected amine in the para -postion for improved phos-phodiester alkylation.39The 10-step synthesis was ac-complished as shown in Scheme 2.Acetophenone 9was obtained in two steps via the O-acylation 40of com-mercially available 2,5-dimethyl phenol 7followed by Fries rearrangement.41Bromo-ketone 10was obtained via R -keto halogenation 42of 9followed by reductive deoxygenation 43to yield 11.Amine hydrochloride 13was easily made in two steps from azide addition 44to 11followed by hydrogentation 45of 12.Functionalization of amine hydrochloride 13with di-tert -butyl dicarbonate 46provided the cinnimate precursor 14.Treatment of 14with bis(pyridine)iodonium tetrafluoroborate 47followed by Heck reaction using methyl acrylate 48gave 16in two

additional steps.Quinone methide precursor 1was then obtained from magnesium reduction 49of R , -unsaturated ester 16.This synthetic pathway was similarly applied to prepare 1′.

Regiospecific Oxidation of 1and 1′to Quinone Methides 2and 2′.The regiospecific generation of p -quinone methides using lead(II)oxide and silver(I)oxide from phenol precursors has been demonstrated.50-52It has been shown in our laboratory that phenolic derivatives functionalized equally at the ortho -and para -positions will oxidize specifically to the p -quinone meth-ide.39This oxidative specificity has allowed derivation of the quinone methide starting from phenolic precursors rather than the catechol precursors used in our previous work,17which proved to be a key factor in greatly enhancing the product stability in this work (vida infra).The conversion of 1and 1′to p -quinone methides 2and 2′was monitored by 1H NMR in CDCl 3at 20°C.The reaction with lead(II)oxide was quantitative and regio-specific for p -quinone methides 2and 2′as determined by relative integration of the p -quinone methide alkyl-idene resonance at 6.42ppm (1H)relative to an internal standard of mesitylene (Ar-H,6.79ppm,3H)(see Ex-perimental Section).There was no sign of lactonization observed in either the preparation of 1or the conversion

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S CHEME

1

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of 1to quinone methide 2,verifying that the methyl propionate with the accompanying o -methyl would not undergo lactonization in competition with quinone meth-ide formation under the oxidative conditions used.

Alkylation of Dibutyl Phosphate by Quinone Methides 2and 2′(UV Analysis).The effect of the methyl substituent on the rate of quinone methide alkylation of a phosphodiester was initially investigated.It was unclear whether the methyl substituent would effect a slower rate for quinone methide alkylation due to a 1,3-allylic steric inhibition or increase the rate by increasing the reactivity of the quinone methide through the same interaction.Previous efforts in our laboratory have utilized both UV and 1H NMR spectroscopy for the determination of p -quinone methide alkylation rates of simple phosphodiesters.16,53Our more recent work has focused on maximizing the rate of quinone methide phosphodiester alkylation.It was determined that incor-poration of an NHBOC functional group in close proxim-ity to the p -benzylic position of the desired p -quinone methide allowed for maximum alkylation rates of simple phosphodiesters.39The enhanced reactivity of the p -quinone methide toward phosphodiester alkylation precluded the ability to monitor the rate of phosphodi-ester alkylation by 1H NMR.To quantify the alkylation rates of quinone methides 2and 2′the reactions were monitored in triplicate by UV spectroscopy,following the loss of quinone methide (λmax )304nm)as a measure of the rate of phosphotriester formation during the initial 60%loss of quinone methide.These reactions were conducted in CH 3CN at 20°C by micropipet addition of 800,600,400,and 200μM solutions (1mL)of serial diluted dibutyl phosphate (2equiv)to 400,300,200and 100μM (1mL)solutions of quinone methide/sodium

perchlorate (0.1M)in a temperature-controlled UV cuvette (200,150,100and 50μM final concentrations of quinone methide).A large excess of sodium perchlorate is required to buffer the change in ionic strength due to formation of the dibutyl phosphate salt in the equilibrium of quinone methide and trialkyl phosphate.The loss of absorbance of the quinone methide was found to be linear with respect to time for the first 60%loss.The linear nature of quinone methide loss indicates no product equilibrium over the monitored course of the reaction (120s)under the conditions of these UV experiments.A control reaction under acid-catalyzed conditions was used to determine if quinone methide hydrolysis was contributing to the observed rate of loss of quinone methide.Based on earlier work,the control reaction used methane sulfonic acid (2equiv)and water (2equiv)to activate the quinone methide toward acid-catalyzed hydrolysis 53but resulted in no quinone methide loss after 2min,suggesting hydrolysis is not a competitive reaction during the monitored analysis.However,upon addition of 2equiv of dibutyl phosphate (containing 2equiv of water)complete loss of the quinone methide absorption signal is observed within 120s at all concentration levels.Based on this UV analysis,the rate of quinone methide disappearance is 1.95×10-2μM -1s -1for 2and 2.03×10-2μM -1s -1for 2′(Figure 2).The negligible difference in the rates of reaction for quinone methides 2and 2′suggests there is not a significant allylic inhibitory effect on quinone methide alkylation for 2.

Lactonization of Phosphotriesters 3and 3′(1

H NMR Analysis).Generation of quinone methides 2and 2′was carried out as described in Experimental Section.The conversion of quinone methide 2′to trialkyl phosphate 3′was clearly observed by 1H NMR analysis upon addition of dibutyl phosphate (2equiv).The disap-(53)Zhou,Q.;Turnbull,https://www.wendangku.net/doc/df18390864.html,.Chem.1999,64,2847-2851.S CHEME 2

a

a

Reaction conditions,%isolated yields:(a)Ac 2O,TEA,CH 2Cl 2,98%;(b)AlCl 3,MeNO 2,75%;(c)CuBr 2,EtOAc,CHCl 3,79%;(d)NaBH 3CN,TFA,70%;(e)NaN 3,EtOH,78%;(f)Pd -C,H 2,HCl,EtOH,72%;(g)di-tert -butyl dicarbonate,TEA,MeOH,83%;(h)Ipy 2BF 4,CH 2Cl 2,DMSO,74%;(i)methyl acrylate,Pd(OAc)2,NMP,TEA,NaOAc,66%;(j)Mg,MeOH,81%.

Improved Phosphotriester Formation https://www.wendangku.net/doc/df18390864.html,.Chem ,Vol .70,No .11,20054341

pearance of the characteristic p -quinone methide alky-lidene resonance of 2′at 6.21ppm (t,J )7.18Hz,1H)coincided with the appearance of a triplet of doublets at 5.20ppm (td,J H -P ) 3.72Hz,1H).This resonance coupling and chemical shift is characteristic of the phosphorus-coupled benzylic proton resonance of the trialkyl phosphate and clearly revealed that phosphodi-ester alkylation had occurred.17,39

The rates of lactonization for alkylation products 3and 3′were obtained from 1H NMR monitored analysis of the reaction in CDCl 3.This was most accurately accom-plished by monitoring the loss of the methyl ester at 3.68ppm (s,3H)in 3and 3′.No other side reaction was seen to occur with the methyl ester other than lacton-ization,as evident by the 1:1ratio of loss in methyl ester resonance with corresponding formation of lactone prod-uct.The rate of lactonization was measured by comparing the methyl ester resonance disappearance relative to an internal standard of mesitylene at 35°C.

The 1H NMR analysis for the non-meta -methylated derivative 3′revealed no sign of lactonization in 1h at 35°C as evidenced by the fact that there was no loss of the methyl ester resonance for trialkyl phosphate 3′.After 2h of heating,10%of the characteristic methyl ester resonance had been https://www.wendangku.net/doc/df18390864.html,plete loss of methyl ester for trialkyl phosphate 3′was observed after 12h at 35°C.As a result of the extended reaction times required for lactonization of 3′,an unidentified reaction,thought to be a polymerization of the quinone methide,resulted in the signal loss of identifiable product to an as yet unidentified material.However,as this side reaction was not detectable in the initial 2h reaction period,it was considered irrelevant for the purpose of relative comparison of 3′as a control for 3(vida infra).The conversion of quinone methide 2to trialkyl phos-phate 3was clearly observed by 1H NMR analysis upon addition of dibutyl phosphate (2equiv).The disappear-ance of the characteristic p -quinone methide alkylidene resonance of 2at 6.42ppm (t,J )7.18Hz,1H)coincided with the appearance of a triplet of doublets at 5.52ppm (td,J H -P )3.24Hz,1H).The in situ lactonization of trialkyl phosphate 3was carefully monitored by 1H NMR analysis during the 2h required for the lactonization reaction to reach completion.

In contrast to nonmethylated trialkyl phosphate 3′,after 1h at 35°C,50%of methylated trialkyl phosphate 3had been converted to lactonized trialkyl phosphate 5,as measured by the loss of methyl ester resonance,relative to the mesitylene internal standard,and as characterized by the appearance of the triplet of doublets at 5.57ppm (td,J P -H )3.24,1H),consistent with the resonance signal of the phosphorus-coupled benzylic hydrogen.There was also a small amount of benzyl alcohol 6produced within the initial hour at 35°C,as evident by the slight appearance of a resonance signal at 5.04ppm,consistent with the benzylic hydrogen.After 2h complete conversion of trialkyl phosphate 3to lactonized trialkyl phosphate 5and benzyl alcohol 6was observed.

The relative rate of lactonization (as measured by the loss of methyl ester)was determined for the conver-sion of phosphotriester 3and benzyl alcohol 4at 35°C in CDCl 3to form 5and 6.The relative rate of lactoniza-tion for the first 60%loss of methyl ester is 6.72×10-4mM s -1.

The final ratio of lactonized trialkyl phosphate 5to benzyl alcohol 6was determined by 1H NMR analysis against a mesitylene internal standard to be 3.0:1.0in favor of the desired trialkyl phosphate based on an average of triplicated runs.This ratio was observed after lactonization was complete in 2h at 35°C.The reaction was allowed to continue for an additional 10h at 35°C to duplicate the conditions used in the control reaction with 3′,and the ratio remained unchanged within that time,as did the quantity of 5and 6relative to the internal standard.This clearly concurs with earlier work 16showing that hydrolysis occurs directly on the quinone methide leading to benzyl alcohol 4,which lactonizes to 6.While 3may revert back to quinone methide 2to undergo hydrolysis prior to lactonization,once lactonization to 5occurs,the trialkyl phosphate product is stable under the reaction conditions.Further,5was found to be stable in CDCl 3(with 2equiv of water)for up to 20days at 20°C,and no change was observed in the ratio of lactonized trialkyl phosphate 5to benzyl alcohol 6.

Whereas our previous catechol-derived system verified the concept of trapping the trialkyl phosphate from quinone methide alkylation of a phosphodiester through lactonization,17this work offers significant improvement in both the rate of lactonization and the stability of

the

F IGURE 2.Plot of the relative rates of the loss of quinone

methide 2and 2′.This demonstrates that the effect of the m -methyl substituent affords a negligible decrease in the rate of quinone methide alkylation.(2)Quinone methide 2′,slope:2.03×10-2μM -1s -1(R 2)0.987).(9)Quinone methide 2,slope: 1.95×10-2μM -1s -1(R 2)0.999).The percent error was determined to be less than 12%for each of the triplicated measurement

points.

F IGURE 3.Loss of methyl ester concomitant with formation

of lactonized trialkyl phosphate 5and benzyl alcohol 6.Each data point was based on relative resonance integration against an internal standard (mesitylene)of at least three independent analyses,as described in the experimental,affording a 5%error,with a slope )6.72×10-4mM s -1(R 2)0.997).

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resulting product.Final demonstration of product stabil-ity was shown by isolation of desired lactonized trialkyl phosphate5using standard silica gel preparative TLC to afford a61%yield of the product.

Conclusion

We have synthesized and compared the rates of quinone methide alkylation of a phosphodiester followed by lactonization of the resulting trialkyl phosphate for two functionalized quinone methides.Our UV and 1H NMR studies demonstrate that incorporation of a methyl group ortho to the propionic ester lactionization functionality still allows for the quantitative,oxidative formation of the p-quinone methide and has a negligible effect on the rate of phosphodiester alkylation with quinone methide2but significantly improves the ensuing lactonization rate of resulting trialkyl phosphate3to afford the stable,lactonized trialkyl phosphate5.Stabil-ity of trialkyl phosphate5has also been improved relative to our previous work with catechol-derived quinone methide alkylators.17Consequently,the overall yield of isolable trialklyphosphate relative to hydrolyzed product increases in favor of the desired trialkyl phos-phate.However,to more effectively compete with revers-ibility of the phosphodiester alkylation with a p-quinone methide,a yet more facile lactonization process would be desired if p-quinone methide formation were not hindered.These results offer further improvements toward the development of a fully functional DNA phos-phodiester alkylating reagent.

Experimental Section

1H NMR analysis was carried out in CDCl3on a270NMR spectrometer.UV data were recorded at304nm in CH3CN using a UV-vis spectrometer.

Acetic Acid2,5-Dimethyl-phenyl Ester8.Triethylamine (24.4mL,164mmol)and acetic anhydride(6.18mL, 65.5mmol)were added to a stirring solution of7(6.67g, 54.6mmol)in CH2Cl2(50mL)at room temperature and stirred for12h.The reaction was diluted with EtOAc,washed with H2O and brine,dried(MgSO4),and concentrated in vacuo to yield a clear oil.The oil was purified by flash chromatography on silica gel(1:1EtOAc/hexanes)to afford a clear oil(8.78g, 98%yield):1H NMRδ7.14(d,J)7.7Hz,1H),6.99(d,J) 7.7Hz,1H),6.85(s,1H),2.34(s,3H),2.32(s,3H),2.16 (s,3H);13C NMRδ169.4,149.3,137.0,130.9,126.9,125.6, 122.5,21.0,20.9,15.8;IR(NaCl)2925,1767,1217cm-1.Anal. Calcd for C10H12O2:C,73.20;H,7.31.Found:C,72.98;H, 7.12.

1-(4-Hydroxy-2,5-dimethyl-phenyl)-ethanone9.Alumi-num chloride(10.3g,76.8mmol)was added to a stirring solution of8(5.04g,30.7mmol)in nitromethane(100mL)at 0°C and subsequently stirred at50°C in an oil bath for12h. The reaction was quenched by pouring over ice(50mL).The yellow solution was then extracted with EtOAc,washed with 6N HCl,saturated NaHCO3,and brine,dried(MgSO4),and concentrated in vacuo to yield a yellow solid.The solid was purified by flash chromatography on silica gel(1:3EtOAc/ hexanes)to afford an off-white solid.The off-white solid was then recrystallized from EtOAc/hexanes to yield a white solid (3.78g,75%yield):mp130-132°C;1H NMRδ7.59(s,1H), 6.67(s,1H),2.56(s,3H),2.49(s,3H),2.25(s,3H);13C NMR δ200.7,157.6,140.1,134.3,129.4,121.2,118.6,29.1,22.2,15.5; IR(NaCl)3431,1640,1280cm-1.Anal.Calcd for C10H12O2: C,73.20;H,7.31.Found:C,73.40;H,7.42.

2-Bromo-1-(4-hydroxy-2,5-dimethyl-phenyl)-etha-none10.A solution of9(1.86g,11.4mmol)in CHCl3(60mL)was added to a refluxing solution of copper(II)bromide (5.07g,22.7mmol)in EtOAc(50mL).The mixture was refluxed for10h.The solution was filtered through charcoal/ Celite and concentrated in vacuo to a green solid.The solid was purified by flash chromatography on silica gel(1:2EtOAc/ hexanes)to afford a light yellow solid.The solid was recrystal-lized from EtOAc/hexanes to yield clear plate crystals(2.19g, 79%):mp141-144°C;1H NMRδ7.55(s,1H),6.66(s,1H), 5.28(s,1H),4.39(s,2H),2.49(s,3H),2.25(s,3H);13C NMR δ192.3,157.5,141.6,133.7,126.6,121.1,118.9,33.5,21.9,15.4; IR(NaCl)3408,1648,1269cm-1.Anal.Calcd for C10H11BrO2: C,49.43;H,4.53;Br,32.88.Found:C,49.62;H,4.64;Br, 33.04.

4-(2-Bromo-ethyl)-2,5-dimethyl-phenol11.Sodium cy-ano-borohydride(2.06g,39.0mmol)was added over10min to a stirring solution of10(2.37g,9.74mmol)in trifluoroacetic acid(30mL)at0°C and stirred for3h.The solution was concentrated in vacuo to yield a yellow oil.The oil was diluted in EtOAc,washed with saturated NaHCO3and brine,dried (MgSO4)and concentrated in vacuo to a slight yellow oil.The oil was purified by flash chromatography on silica gel (1:3EtOAc/hexanes)to afford a clear oil(1.56g,70%):1H NMR δ6.91(s,1H),6.59(s,1H),5.03(s,1H),3.48(t,J)7.92Hz, 2H),3.05(t,J)7.92Hz,2H),2.24(s,3H),2.20(s,3H); 13C NMRδ152.6,135.0,132.2,129.5,121.5,117.1,36.3,32.4, 19.0,15.4;IR(NaCl)3418,1283cm-1.Anal.Calcd for C10H13-BrO:C,52.45;H,5.68;Br,34.89.Found:C,52.52;H,5.55; Br,34.67.

4-(2-Azido-ethyl)-2,5-dimethyl-phenol12.Sodium azide (0.858g,13.2mmol)was added to a stirring solution of11 (2.52g,11.0mmol)in ethanol(60mL)and refluxed for10h. The mixture was passed through Celite and concentrated in vacuo to yield a clear oil.The oil was diluted in EtOAc,washed with H2O and brine,dried(MgSO4),and concentrated in vacuo to a clear oil.The oil was purified by flash chromatography on silica gel(1:3EtOAc/hexanes)to afford a clear oil(1.64g, 78%):1H NMRδ6.93(s,1H),6.60(s,1H),5.42(s,1H),3.40 (t,J)7.67Hz,2H),2.79(t,J)7.67,2H),2.26(s,3H),2.23 (s,3H);13C NMRδ152.6,135.0,132.2,128.2,121.7,117.1, 51.9,31.9,19.0,15.5;IR(NaCl)3408,2100,1282cm-1.Anal. Calcd for C10H13N3O:C,62.85;H,6.80.Found:C,62.79;H, 7.00.

2-(4-Hydroxy-2,5-dimethyl-phenyl)-ethylammonium Chloride13.Palladium/carbon(10%,0.325g,20%w/w)and concentrated hydrochloric acid(1mL)were added to a solution of12(1.63g,8.51mmol)in ethanol(20mL)in a high-pressure flask.The solution was hydrogenated under H2pressure (60psi)with shaking for8h.The solution was passed through Celite and concentrated in vacuo to an off-white solid.The solid was recrystallized from EtOH/Et2O to yield white crystals (1.23g,72%):mp218-222°C;1H NMRδ6.86(s,1H),6.59 (s,1H),3.03(t,J)5.69,2H),2.83(t,J)5.69,2H),2.23 (s,3H),2.12(s,3H);13C NMRδ154.2,134.3,131.5,125.1, 122.1,116.5,40.0,30.1,17.6,14.4.

[2-(4-Hydroxy-2,5-dimethyl-phenyl)-ethyl]-carbamic Acid tert-Butyl Ester14.Di-tert-butyl dicarbamate (0.734g,3.37mmol)was added to a stirring solution of13 (0.566g,2.80mmol)in TEA/MeOH(1:3,10mL)at room temperature and stirred for7h.The solution was diluted with EtOAc,washed with saturated ammonium chloride and brine, dried(MgSO4),and concentrated in vacuo to a light brown solid.The solid was recrystallized from EtOAc/hexanes to yield clear crystals(0.620g,83%):mp160-162°C;1H NMRδ6.85 (s,1H),6.58(s,1H),4.56(bs,1H),3.28(bq,J)6.68,2H), 2.68(t,J)6.68,2H),2.22(s,3H),2.18(s,3H),1.43(s,9H); 13C NMRδ156.0,152.3,135.2,132.3,129.1,121.0,116.9,79.4, 41.1,32.8,28.5,19.0,15.3;IR(NaCl)3328,1684,1516,1282, 1166cm-1.Anal.Calcd for C15H23NO3:C,67.95;H,8.68. Found:C,68.12;H,8.54.

[2-(4-Hydroxy-3-iodo-2,5-dimethyl-phenyl)-ethyl]-car-bamic Acid tert-Butyl Ester15.Bis(pyridine)iodonium tetrafluoroborate(0.844g,2.23mmol)was added to a stirring

Improved Phosphotriester Formation

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solution of14(0.547g,2.06mmol)in DMSO/CH2Cl2(1:10, 25mL)at room temperature and stirred for9h.The solution was diluted with EtOAc,washed with H2O and brine,dried (MgSO4),and concentrated in vacuo to a yellow oil.The oil was purified by flash chromatography on silica gel(1:3EtOAc/ hexanes)to afford a pale yellow oil(0.598g,74%):1H NMR δ6.84(s,1H),5.45(s,1H),4.59(bs,1H),3.25(q,J)6.68, 2H),2.80(t,J)6.68,2H),2.42(s,3H),2.26(s,3H),1.43 (s,9H);13C NMRδ156.0,151.5,137.0,132.5,129.6,121.8, 95.9,79.3,41.3,34.8,28.5,25.3,16.9;IR(NaCl)3402,2248, 1693cm-1.Anal.Calcd for C15H22INO3:C,46.05;H,5.67. Found:C,46.26;H,5.59.

3-[3-(2-tert-Butoxy carbonylamino-ethyl)-6-hydroxy-2,5-dimethyl-phenyl]-acrylic Acid Methyl Ester16.Pal-ladium acetate(0.017g,0.076mmol),TEA(0.580mL, 3.80mmol),and NMP(10mL)were combined in a test tube and heated to dissolve the palladium.The black solution was then added to a stirring mixture of15(0.598g,1.52mmol), sodium acetate(0.125g,1.52mmol),and NMP(10mL)in a high-pressure reaction tube.The solution was stirred while heating at75°C in an oil bath for14h.The mixture was diluted with EtOAc,washed with H2O and brine,dried (MgSO4),and concentrated in vacuo to a dark brown solid.The solid was purified by flash chromatography on silica gel (1:3EtOAc/hexanes)to afford a light brown solid.The solid was recrystallized from EtOAc/hexanes to yield clear crystals (0.352g,66%):mp168-170°C;1H NMRδ7.83(d,J)16.33 Hz,1H),6.90(s,1H),6.41(d,J)16.33Hz,1H),5.21(s,1H), 4.56(bs,1H),3.81(s,3H),3.23(bq,J)6.68,2H),2.73(t,J) 6.68,2H),2.25(s,3H),2.21(s,3H),1.43(s,9H);13C NMR δ167.4,156,150.8,141.0134.1,133.2,129.2123.3,121.5, 121.2,79.2,51.9,41.2,33.6,28.5,16.2,15.8;IR(NaCl)3404, 1644cm-1.Anal.Calcd for C19H27NO5:C,65.36;H,7.73. Found:C,65.15;H,7.59.

3-[3-(2-tert-Butoxycarbonyl)amino-ethyl)-6-hydroxy-2,5-dimethyl-phenyl]-propionic Acid Methyl Ester 1. Magnesium turnings dried at80°C(0.010g,0.421mmol)were added to a stirring solution of16(0.015g,0.042mmol)in dry MeOH(1mL)at room temperature and stirred for8h.Acetic acid(0.200mL)was added to the solution and then diluted with EtOAc,washed with saturated NaHCO3and brine,dried (MgSO4),and concentrated in vacuo to a light yellow solid.The solid was recrystallized from EtOAc/hexanes to yield clear crystals(0.008g,81%):mp136-139°C;1H NMRδ7.37 (s,1H),6.80(s,1H),4.57(bs,1H),3.68(s,3H),3.23(q,J) 6.68,2H),2.95(t,J)5.69,2H),2.68(m,4H),2.20(s,3H), 2.18(s,3H),1.43(s,9H);13C NMRδ176.6,156.0,151.5,132.9, 130.6,129.0,126.0,123.4,79.3,52.4,41.2,34.0,33.6,28.5,21.4, 16.3,15.0;IR(NaCl)3376,2977,1695cm-1.Anal.Calcd for C19H29NO5:C,64.93;H,8.32;N,3.99.Found:C,64.63;H, 8.27;N,3.87.

Quinone Methide2and2′Solutions For UV Studies. In separate vials,solutions of phenol1(2.0mg,5.6μmol)and 1′(1.9mg,5.6μmol)in CH3CN(10mL)were oxidized with lead(II)oxide(14mg)by stirring at20°C for20min.The suspension of each was filtered through a13mm syringe filter with0.45μm PTFE membrane to give quinone methides2and 2′as separate solutions.

Study of Quinone Methide2and2′Reaction in Dibutyl Phosphate/Acetonitrile Solution(2equiv,20°C). The560μM stock solutions of quinone methide2and2′were serial diluted to concentrations of400,300,200,and100μM. The400μM solution was prepared by adding7.14mL of stock quinone methide to a10mL volumetric flask with a1000 micropipet.To this solution was then added2.45mL of NaClO4 solution(0.1M,1.0g NaClO4/10mL CH3CN).The solution was then diluted with CH3CN to give a final volume of10mL. To prepare the300,200,and100μM quinone methide solutions0.620,0.820,and1.23mL aliquots of NaClO4solution were added to each volumetric flask prior to dilution.The final concentration of NaClO4in each solution was0.1M.A stock solution(26.9mM,10mL)of dibutyl phosphate was prepared by diluting the phosphate(50μL,269μmol)in10mL of CH3CN.The stock solution was then diluted to concentrations of800,600,400,and200μM(2equiv relative to the quinone methide solution)in10mL volumetric flasks with CH3CN.The volumetric flasks were allowed to equilibrate in a20°C water bath prior to UV analysis.A1mL aliquot of quinone methide solution was combined with1mL of the corresponding dibutyl phosphate solution(2equiv)to give four reactions with final concentrations of quinone methide of200,150,100,and 50μM.The disappearance of the quinone methide was measured atλmax of304nm,where there was no other interfering absorbance signal.All experiments were performed in triplicate.The rates(k obs)of loss of quinone methide2and 2′were based upon their decaying absorbance signal recorded every500ms.The rates were determined in the first60%loss of absorbance signal as the slope of ln A/t.

A control reaction containing an equimolar mixture of methane sulfonic acid(2equiv)and water(2equiv),similarly prepared as the dibutyl phosphate solutions,was added to the quinine methide at all concentration levels.The quinone methide absorbance signal(λmax of304nm)revealed no decay after2min,suggesting that acid-catalyzed hydrolysis is not competitive with phosphate alkylation under the reaction conditions.

Quinone Methide2and2′for NMR Studies.A22mM solution of phenol1(5.0mg phenol/0.65mL CDCl3)or1′(4.8mg phenol/0.65mL CDCl3)and1equiv mesitylene(2μL, 14.3μmol)were combined with lead(II)oxide(34mg)with stirring at20°C for20min.The suspensions were filtered as described above to afford a yellow solution of quinone methide. The reaction with lead(II)oxide was quantitative for p-quinone methides2and2′as determined by relative integration of the p-quinone methide alkylidene resonance at6.42ppm(1H) relative to an internal standard of mesitylene(Ar-H,6.79ppm, 3H).Quinone methide2:1H NMR(CDCl3,270MHz)δ7.22 (s,1H),6.42(t,J)7.18,1H),4.21(t,J)6.18,2H),3.65 (s,3H),2.84(t,J)8.15,2H),2.41(t,J)8.15,2H),2.18 (s,3H),1.99(s,3H),1.45(s,9H).Quinone methide2′:1H NMR (CDCl3,270MHz)δ7.29(s,1H),6.88(s,1H),6.21(t,J)7.18, 1H),4.16(t,J)6.43,2H),3.65(s,3H),2.71(t,J)8.15,2H), 2.57(t,J)8.15,2H),2.02(s,3H),1.45(s,9H).

To the quinone methide solution was added2equiv of dibutyl phosphate(5.3μL,28.6μmol).The conversion of quinone methide2or2′to trialkyl phosphate3or3′was monitored by1H NMR analysis upon addition of dibutyl phosphate.Trialkyl phosphate3:1H NMRδ7.07(s,1H),5.52 (td,J P-H)3.24,1H),4.04-3.88(m,4H),3.86(t,2H),3.68 (s,3H),2.94(t,J)6.91,2H),2.67(t,J)6.67,2H),2.25 (s,3H),2.21(s,3H),1.62(m,4H),1.45(s,9H),1.31(m,4H), 0.89(m,6H).Trialkyl phosphate3′:δ6.99(s,1H),6.92 (s,1H),5.20(td,J P-H)3.72,1H),4.04-3.88(m,4H),3.89 (t,2H),3.68(s,3H),2.84(t,J)6.45,2H),2.69(t,J)6.67, 2H),2.23(s,3H),1.62(m,4H),1.45(s,9H),1.31(m,4H),0.89 (m,6H).

Trialkyl phosphate3′was cleanly observed in the initial 1H NMR spectra.The conversion of trialkyl phosphate3′to lactonized trialkyl phosphate5′was monitored by comparison of the relative integration of methyl ester at3.68ppm(s,3H) to an internal standard of mesitilyene(Ar-H,6.79ppm,3H) at35°C in CDCl3in five min.intervals for120min.During the first hour of lactonization monitoring the emergence of presumed benzyl alcohol4′is observed at4.9ppm with no measurable loss of methyl ester at3.68(s,3H).After2h10% of the methyl ester resonance signal had been lost and the ratio of trialkyl phosphate3′to presumed benzyl alcohol4′(based on its close1H NMR correspondence to4and6)is approximately3:1.After2h of monitoring,a slight decrease in signal intensity was observed for presumed trialkyl phos-phate3′and benzyl alcohol4′resonances relative to the integration of the internal standard.The reaction conditions (CDCl3,35°C)were maintained for an additional10h. 1H NMR analysis of the reaction mixture revealed the complete

Bakke et al.

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loss of the methyl ester resonace signal and less than30%of the combined characteristic signal intensity remained for presumed lactonized trialkyl phosphate5′and benzyl alcohol 6′(based on their close1H NMR correspondence to5and6). The scale of the reaction and limited observable material prevented isolation and definitive characterization of lacton-ized trialkyl phosphate5′and benzyl alcohol6′.Additional, unidentified resonance signals were observed in the final 1H NMR spectrum.

The conversion of trialkyl phosphate3to lactonized trialkyl phosphate5was monitored by comparison of the relative integration of the resonance signal consistent with the methyl ester at3.68ppm(s,3H)to a resonance signal for the internal standard of mesitilyene(Ar-H,6.79ppm,3H)at35°C in CDCl3in five min.intervals for120min.During the first hour of lactonization monitoring,the triplet of doublets at5.52ppm (J H-P) 3.24Hz,1H)from3began to overlap with the emerging triplet of doublets at5.57ppm(td,J P-H)3.24,1H), characteristic of lactonized trialkyl phosphate5.Concurrent with the formation of the triplet of doublets at5.57ppm for5 was the disappearance of the resonance signal for the aromatic proton at7.07(s,1H)of3and subsequent emergence of a resonance signal of an aromatic proton at7.18(s,1H) consistent with the formation of5.Additionally,during the first hour of lactonization monitoring,the slight appearance of a resonance signal at5.04ppm and a singlet at7.28ppm was observed consistent with the formation of benzyl alcohol 6.After2h,based on analysis of the already described resonance signals,complete conversion of quinone methide2 to lactonized trialkyl phosphate5and lactonized benzyl alcohol 6was observed in a3.0:1.0ratio favoring trialkyl phosphate 5.The reaction conditions(CDCl3,35°C)were maintained for an additional10h.No measurable change was detected in the ratio of lactonized trialkyl phosphate5and benzyl alcohol6 following the completion of the lactonization reaction in the initial2h.This was determined by comparison of the relative integration of the aromatic proton of trialkyl phosphate5at 7.18with the aromatic proton of benzyl alcohol6at7.28ppm and the triplet of doublets of trialkyl phosphate5at5.57ppm with the multiplet of benzyl alcohol6at5.04to an internal standard of mesitilyene(Ar-H,6.79ppm,3H).The rate of lactonization was calculated as the slope of concentration of methyl ester(mM)vs time(min.)for the first60%of methyl ester resonance signal loss.All experiments were performed in triplicate.

Lactonized Trialkyl Phosphate5.A22mM solution of phenol1(5.0mg phenol/0.65mL CHCl3)was stirred with lead-(II)oxide for20min.The suspension was filtered as described above to yield a yellow solution of quinone methide.To the resulting quinone methide solution was added2equiv of dibutyl phosphate(5.3μL,28.6μmol),and the resulting solution was stirred at35°C for2h.The mixture was concentrated in vacuo to yield a crude oil.The desired product was isolated via preparative TLC(3:1EtOAc/hexanes)to yield a semi-white solid(4.8mg,61%):1H NMRδ7.18(s,1H),5.57 (td,J P-H)3.24,1H),3.96(m,4H),3.53-3.44(bm,1H),3.31-3.19(bm,1H),2.94(t,J)6.91,2H),2.73(t,J)6.91,2H), 2.27(s,3H),2.26(s,3H),1.62(m,4H),1.44(s,9H),1.31 (m,4H),0.89(m,6H);13C NMRδ171.3,156.0,148.2,135.7, 134.0,132.6,129.2,126.4,79.3,74.2,63.8,47.3,32.1,29.7,28.5, 21.4,18.7,16.3,15.0,13.1.Anal.Calcd for C26H42NO8P:C, 59.19;H,8.02;N,2.65.Found:C,59.41;H,8.22;N,2.83.

Lactonized Benzyl Alcohol6.1H NMRδ7.28(s,1H),5.04 (bm,1H),3.40(ddd,J)2.97,1H),3.12(m,1H),2.93(t,J) 6.91,2H),2.73(t,J)6.91,2H),2.27(s,3H),2.23(s,3H),1.45 (s,9H).

Acetic Acid o-Tolyl Ester8′.14.3g,99%;1H NMRδ7.18 (m,3H),7.03(d,1H),2.32(s,3H),2.20(s,3H);13C NMR δ169.3,149.5,131.2,130.2,127.0,126.1,122.0,20.9,16.2; IR(NaCl)1761,1213cm-1.Anal.Calcd for C9H10O2:C,71.98; H,6.66.Found:C,71.82;H,6.80.

1-(4-Hydroxy-3-methyl-phenyl)-ethanone9′.11.3g,76%; mp106-109°C;1H NMRδ7.79(s,1H),7.74(d,J)8.41Hz, 1H),7.39(s,1H),6.88(d,J)8.41Hz,1H),2.57(s,3H),2.29 (s,3H);13C NMRδ198.7,159.6,132.1,129.6,128.8,124.6, 114.9,26.4,16.0;IR(NaCl)3252,1652,1591,1281cm-1.Anal. Calcd for C9H10O2:C,71.98;H,6.66.Found:C,72.14;H,6.80.

2-Bromo-1-(4-hydroxy-3-methyl-phenyl)-ethanone10′.

3.44g,72%;mp118-20°C;1H NMRδ7.80(s,1H),7.76 (d,J)8.41Hz,1H),6.85(d,J)8.41Hz,1H),5.95(s,1H),

4.39(s,2H),2.29(s,3H);13C NMRδ190.7,159.4,132.6,129.4, 126.9,124.7,11

5.2,30.8,15.9;IR(NaCl)3386,1670,1587. Anal.Calcd for C9H9BrO2:C,47.19;H, 3.93;Br,34.88. Found:C,47.30;H,4.03;Br,34.64.

4-(2-Bromo-ethyl)-2-methyl-phenol11′. 2.27g,79%; 1H NMRδ6.95(s,1H), 6.90(d,J)8.41Hz,1H), 6.69 (d,J)8.41Hz,1H),4.39(b,1H),3.51(t,J)7.67Hz,2H), 3.05(t,J)7.67Hz,2H),2.23(s,3H);13C NMRδ152.8,131.4, 131.2,127.3,124.2,115.1,38.7,33.6,15.9;IR(NaCl)3415, 1510,1261cm-1.Anal.Calcd for C9H11BrO:C,50.25;H,5.11; Br,37.15.Found:C,50.10;H,5.18;Br,36.94.

4-(2-Azido-ethyl)-2-methyl-phenol12′. 1.57g,89%; 1H NMRδ6.96(s,1H), 6.90(d,J)8.16Hz,1H), 6.70 (d,J)8.16Hz,1H),4.85(s,1H),3.45(t,J)7.18Hz,2H), 2.79(t,J)7.18Hz,2H),2.23(s,3H);13C NMRδ152.7,131.5, 130.2,127.3,124.1,115.2,52.8,34.6,15.9;IR(NaCl)3407, 2102,1509cm-1.Anal.Calcd for C9H11N3O:C,61.00;H,6.21; N,23.71.Found:C,61.20;H,6.33;N,23.58.

2-(4-Hydroxy-3-methyl-phenyl)-ethylammonium Chlo-ride13′.1.19g,72%;mp178-181°C;1H NMRδ6.97(s,1H), 6.89(d,J)8.16,1H),6.71(d,J)8.16Hz,1H),3.10(t,J) 15.09Hz,2H), 2.82(t,J)15.09Hz,2H), 2.17(s,3H); 13C NMRδ154.2,130.8,126.9,126.7,124.8,114.7,41.0,32.5, 14.9.Anal.Calcd for C9H14ClNO:C,57.60;H,7.46;Cl,18.89. Found:C,57.45;H,7.27;Cl,19.03.

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[2-(4-Hydroxy-3-iodo-5-methyl-phenyl)-ethyl]-carbam-ic Acid tert-Butyl Ester15′.2.060g,81%;1H NMRδ7.30 (s,1H),6.90(s,1H),5.27(s,1H),4.54(bs,1H),3.27(q,J) 6.93Hz,2H),2.64(t,J)6.93Hz,2H),2.26(s,3H),1.43 (s,9H);13C NMRδ155.9,151.6,135.6,132.8,132.0,124.9, 86.0,79.4,41.9,34.9,28.5,17.3;IR(NaCl)3356,1693cm-1.

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JO050050S

Improved Phosphotriester Formation

https://www.wendangku.net/doc/df18390864.html,.Chem,Vol.70,No.11,20054345

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