BACKGROUND OF INVENTION

A Smiles rearrangement describes a pattern of reactions involving intramolecular nucleophilic aromatic substitution which results in the migration of one heteroatom to

another on an aromatic ring. The Smiles rearrangement works with a variety of heteroatoms, including oxygen, sulfur and nitrogen. The Smiles rearrangement of

phenols, including fused-ring heterocyclic phenols, into corresponding anilines is described by I.G.C. Coutts and M.R. Southcott in J. Chem. Soc. Perkin Trans. I,

1990;767-771. The syntheses described by Coutts and Southcott replace the hydroxy group on an aromatic ring, optionally fused into a larger ring system, with an amino group. The paper describes the synthesis as a distinct three-step process, with the

purification of each intermediate. The first step is an alkylation of the alcohol into a 2- aryloxyacetamide. The second step is the actual Smiles rearrangement of the aryloxyacetamide into the 2-hydroxy-N-arylacetamide. Finally, the 2-hydroxy-N- arylacetamide is hydrolyzed into the corresponding aromatic amine. The known Smiles

rearrangements of aromatic amides or amines from hydroxy aromatics involve purification of the 2-aryloxyacetamide intermediates.

Methods of direct conversion of phenols to anilines are known, but most have

serious drawbacks. For example, transformations of 4-chloro-2-phenylquinazoline are limited to substrates resistant to high temperatures and basic conditions. Similarly, a method of converting phenols via diethyl phosphate esters requires the use of toxic diethyl chlorophosphate and of potassium in liquid ammonia. The Bucherer reaction is

restricted to naphthalenes and related heterocycles. I.G.C. Coutts and M.R. Southcott J. Chem. Soc. Perkin Trans. I, 1990;767-771. Therefore, there is a need for a general

synthesis of anilines from phenols which is applicable to a broad range of phenols, which doesn't require the use of toxic reagents, requires few steps and produces good yields.

Aromatic amines are of great interest in both the chemical and pharmaceutical

industries. For example, phenacetin, an acetylated ethoxyaniline, is a known analgesic.

Additionally, aromatic amines are useful intermediates for the preparation of more complicated organic molecules. Aromatic amines are used in the preparation of many

commercially important dyestuffs, such as azine, azo and azoxy dyes. Conversion of 3- hydroxy estrogens into their corresponding amines is described by Coutts and M.R.

Southcott, supra.

SUMMARY OF THE INVENTION:

The present invention is an improved method of effecting an alkylation and Smiles rearrangement of a hydroxy aromatic to a 2-hydroxy-N-arylacetamide, where the alkylation and Smiles rearrangement are carried out without purifying the 2-

aryloxyacetamide intermediate. The avoidance of the purification step is significant in terms of minimizing the time, cost and resources necessary during the synthesis of aromatic amines and yet obtains good overall yields.

The present invention is a process of converting a hydroxy aromatic into a 2- hydroxy-N-arylacetamide, comprising the steps of:

(1) treating a reaction mixture comprising a salt of a hydroxy aromatic with an alkylating agent; and

(2) treating the reaction mixture with a Smiles solvent system and raising the temperature of the reaction mixture.

Another embodiment of the process comprises the steps of:

(1) treating a reaction mixture comprising an alkylating solvent system and the a hydroxy aromatic to form a salt;

(2) treating the reaction mixture with an alkylating agent; and

(3) treating the reaction mixture with a Smiles solvent system and raising the temperature of the reaction mixture.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is an improved process of effecting an alkylation and Smiles rearrangement of a hydroxy aromatic to an 2-hydroxy-N-arylacetamide, where the alkylation and Smiles rearrangement are carried out without purifying the 2-

aryloxyacetamide intermediate. First, a salt of the hydroxy aromatic is formed in the presence of an alkylating solvent system, to which an alkylating agent is added. Finally, a Smiles solvent system is added to the reaction mixture containing the 2- aryloxyacetamide intermediate and the reaction mixture is heated to effect the Smiles rearrangement and form the 2-hydroxy-N-arylacetamide product. Optionally, the 2- hydroxy-N-arylacetamide is hydrolyzed to form the corresponding aromatic amine.

Suitable hydroxy aromatics for the present reaction are well known to those

skilled in the art. Hydroxy aromatics are optionally substituted in the ortho, meta and para positions. Preferred ortho substituents include activating groups such as nitro, and

alkoxy, methyl and ethyl groups. Preferred meta and para substituents include nitro,

alkoxy, halogen. C]. ₂ o alkyl and C _{M O} alkoxy. Preferred hydroxy aromatics are

compounds of the formula:

wherein R ¹ , R ² and R ³ are each independently halogen, C| _-2 o alkyl, C _{M O} alkoxy. Hydroxy aromatics may be simple hydroxy aromatics having a single aromatic ring, such as

phenols and substituted alkoxyphenols. Preferred hydroxy aromatics are substituted at the meta and para positions. Complex hydroxy aromatics may also be used in the present invention, where R ¹ and R ^~ or R ^" and R may be combined to formed multiple carbon fused ring structures of varying degrees of saturation, or where ring structures are

attached as substituents. Suitable complex ring structures include fully aromatic complex ring structures such as indene, naphthalene, anthracine, phenanthrene, benzofuran and dibenzofuran, as well as their partially and fully saturated counterparts, such as dihydroindene, 1,2- and 2,3-dihydronaphthalenes, di-, tetra-, hexa- and octa-

hydroanthracine, di-, tetra-, hexa- and octa-hydrophenanthrene, di- and tetra- hydrodibenzofuran. Preferred complex aromatic ring structures include steroids. Specific examples of suitable steroids for use in the invention include naturally occurring steroids and synthetic steroids. Especially preferred are estrogens, of which estradiol,

estrone, 6-, 7-, 8-, 9-, 11-, 14-, 15-dehydroestrone, equilenin and cyclopentaphenanthrene are particularly preferred. Preferred synthetic steroid mimics are triarylethylenes and tamoxifen analogs are particularly preferred. In complex ring structures, the carbon

atoms in the rings other than the those in the hydroxy aromatic ring are optionally

substituted with a wide variety of substituents known to those in the art, including NH ₂ ,

N0 ₂ , SH, , S0 H, CO ₂ H, CN, halogens, thioethers, alkyl, alkoxy groups and other functional groups such as carbamates, ethers, amides, and esters.

The salt of the hydroxy aromatic compound may be formed according to methods well-known in the art. Preferably, the salt of the hydroxy heteroaromatic compound is formed in the presence of an alkylating solvent system, to which an alkylating agent is added.

The alkylating agent serves as a donor of a substituent capable of undergoing intramolecular nucleophilic substitution, or the Smiles rearrangement. Alkylating agents

useful in the present invention are well known to those of ordinary skill in the art.

Generally, suitable alkylating agents are comprised of an amide and halogen functional group separated by two carbon atoms of the following general formula:

(R')(R")(X)-C-C-(O)-NH ₂

wherein X is a leaving group. Suitable leaving groups include halogens and OR, where

R isp-toluenesulfonyl or methylsulfonyl. A preferred leaving group is selected from

bromine, chlorine and iodine. An especially preferred leaving group is bromine.

R' and R" of the alkylating agent are independently H or C, _-6 alkyl, straight or branched chain. Only one of R' or R" may be hydrogen. It is preferred that when one of

R' or R" is hydrogen, the other is a larger alkyl such as isopropyl, .veobutyl or r -butyl or equivalent pentyl or hexyl groups. It is especially preferred that when one of R' or R" is hydrogen, the other is tert-butyl. C|. ₆ alkyl is a straight and branched one to six carbon group including methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl and

hexyl.

A preferred alkylating agent is where X is a halogen and R' and R" is C|. alkyl.

An especially preferred alkylating agent is where X is bromine and at least one of R' and

R" is methyl or ethyl. Preferred alkylating agents are secondary haloalkylamides and, most preferred are tertiary haloalkylamides, with 2-bromo-2-methylpropanamide and 2- bromo-2-ethylbutanamide being especially preferred.

Alkylating solvent system generally comprises a strong base, an ethereal solvent and a large alkaline metal cation.

A strong base is capable of extracting the alcoholic proton of the hydroxy aromatic. A single strong base may be used, or a combination of two or more strong

bases may be used. Suitable strong bases include sodium hydride, potassium hydride, lithium hydride, lithium bis-trimethylsilyl amide, sodium bis-trimethylsilyl amide,

potassium bis-trimethylsilyl amide, n-butyllithium, jec-butyllithium, j ^' sø-butyllithium,

te/r-butyllithium, and mixtures thereof. The hydride bases are preferred, such as sodium hydride, lithium hydride, potassium hydride and mixtures thereof. Sodium hydride is

especially preferred.

An ethereal solvent is used to solvate the reaction components, including the alkylating agent and large alkaline metal cation. The ethereal solvent should be polar and

non-nucleophilic. Suitable ethereal solvents include 1,4-dioxane, 1 ,3-dioxane,

tetrahydrofuran (THF), dimethoxyethane (DME), 2-methoxyethyl ether, propyl ether, isopropyl ether, 77-butyl ether, sec-butyl ether, rert-butyl ether, n-butylmethyl ether, tert- butylmethyl ether, n-butylethyl ether, sec-butylethyl ether, ferf-butylethyl ether, n- butylpropyl ether, sec-butylpropyl ether, terf-butylpropyl ether and mixtures thereof. Preferred ethereal solvents have relatively low boiling points. 1,4-Dioxane and 1,3- dioxane are preferred. 1 ,4-Dioxane is especially preferred.

A large alkaline metal cation is believed to function as an electron transfer facilitator. More specifically, the large metal cation is thought to promote radical

alkylation reactions. Inorganic cesium compounds are preferred. Suitable examples of sources of large alkaline metal cations include cesium carbonate (Cs ₂ CO ₃ ), cesium

acetate (CsCOιCH ₃ ), cesium bicarbonate (CsHCO ₃ ), cesium bromide (CsBr), cesium chloride (CsCl), cesium fluoride (CsF), cesium iodide (Csl). Cesium carbonate is

preferred.

A Smiles solvent system is added to the reaction mixture to promote the Smiles rearrangement. The Smiles solvent system is designed to solvate the reagents, act as an

anion-coordinating agent by promoting and/or stabilizing the anionic form of the 2-

aryloxyacetamide intermediate and to coordinate or make the 2 -aryloxyacetamide intermediate a stronger nucleophile, through conversion into an anion, and thus facilitating a Smiles rearrangement.

A Smiles solvent system comprises an amide solvent, an anion-coordinating agent and a strong base. Preferably, there are at least molar equivalents of the anion- coordinating agent to alkaline metal cation.

The Smiles solvent system may be premixed or each component added sequentially to the reaction mixture in any order.

A strong base is capable of extracting the amide proton of the 2-aryloxyacetamide intermediate. A single strong base or a combination of two or more strong bases may be used in the present invention. Suitable strong bases include sodium hydride, potassium hydride, lithium hydride, lithium bis-trimethylsilyl amide, sodium bis-trimethylsilyl

amide, potassium bis-trimethylsilyl amide, n-butyllithium, sec-butyllithium, iso-

butyllithium, terr-butyllithium or mixtures thereof. The hydride bases are preferred, such as sodium hydride, lithium hydride and potassium hydride. Sodium hydride is especially

preferred. The strong base may be the same strong base used as the strong base for alkylation.

The amide solvent is preferably l-methyl-2-pyrrolidinone (NMP),

dimethylformamide (DMF), dimethylacetamide (DMA) or mixtures thereof. NMP is preferred amide solvent.

The anion-coordinating agent may be N, N'-dimethyl-NΝ '-propy leneurea; also

known as l,3-dimethyltetrahydropyrimidin-2(lH)-one (DMPU) or hexamethylphosphoric triamide (ΗMPA) or a combination thereof. DMPU is the

preferred anion-coordinating agent.

The volume ratio of a amide solvent to a anion-coordinating agent is optionally from about 1 : 1 to about 40: 1. Preferably, the ratio of amide solvent to anion-

coordinating agent is from about 5: 1 to about 15: 1. The ratio of amide solvent to anion- coordinating agent is especially preferred to be between about 7: 1 to about 12: 1. The

most preferred ratio of amide solvent to anion-coordinating agent is about 10: 1.

The salt of the hydroxy aromatic is formed by reacting a hydroxy aromatic in the presence of an alkylating solvent system. The reaction mixture is optionally stirred for a period sufficient to form a salt of the hydroxy aromatic. Preferably, when sodium

hydride is used in the alkylating solvent system, evolution of hydrogen gas continues until the formation of the hydroxy aromatic salt is substantially complete. Preferably, the reaction mixture is heated during the formation of the salt. Higher temperatures

generally require shorter reaction time for the formation of the salt and lower temperatures generally requires longer reaction time.

An alkylating agent is preferably added to the reaction mixture after formation of the hydroxy aromatic salt. In a more preferred embodiment, the reaction mixture is stirred at reflux until substantial completion of the alkylation occurs. Reaction progress of the alkylation may be monitored by known techniques, including thin-layer

chromatography (TLC), gas chromatography (GC) or high performance liquid

chromatography (HPLC). TLC is preferred. After alkylation, a Smiles solvent system, preferably a combination of amide solvent, anion-coordinating agent and strong base, is added to the reaction mixture.

The temperature of the reaction mixture is raised to a temperature sufficient to effect the Smiles rearrangement. Faster reaction time is expected with higher temperatures and longer reaction time is expected with lower temperatures. Preferred

reaction temperature is between about 65°C to about 250°C, preferably between about 125°C to 200°C. A more preferred reaction temperature is between about 125°C to about

175°C. The most preferred reaction temperature is about 150°C. The reaction mixture is optionally stirred during the Smiles rearrangement.

Reaction progress of the Smiles rearrangement is optionally monitored by any

known technique, for example, thin-layer chromatography (TLC), gas chromatography (GC), high performance liquid chromatography (HPLC). TLC is preferred. Upon completion of the Smiles rearrangement, the 2-hydroxy-N-arylacetamide product is purified by known methods.

Optionally, the acylated aromatic may be hydrolyzed under known conditions to give the corresponding aromatic amine.

Example 1 Preparation of 2-Bromo-2-methyl propanamide

To a 1 L Erlenmeyer was added bromoisobutyryl bromide (Aldrich, 23.0 mL,

42.0 g, 0.18 mole) and hexane (500 mL). The mixture was vigorously stirred at 0 °C and

concentrated aqueous NH4OH (EM Scientific, 80 mL) was added in portions over 30

min. The resulting mixture was stirred an additional 30 min. at 0 °C, then the white precipitate was filtered by suction and washed several times with ice water. After drying

on the funnel about lh, the crude product (41.7 g, 0.25 mole, 140% crude yield) was

recrystallized from 200 mL CHCI3 and 20 mL hexane. Product was obtained as shiny

white plates (31.2 g, 0.18 mole, 100%): mp 146-148 °C.

Example 2 Preparation of N-(3-amino-l,3,5,(10)-estratrien-17-one-yI)-2-hydroxy-2- methylpropionamide

To a solution of estrone (1.00 g, 3.70 mmol) in dioxane (20 mL) was added NaH (Aldrich, dry, 300 mg, 12.2 mmol) and CS2CO3 (4.00 g, 12.2 mmol). The resulting

mixture was stirred at room temperature for about 30 minutes, then 2-bromo-2-methyl- propanamide (2.03 g, 12.2 mmol) was added and the resulting mixture was stirred at reflux for 16 h. After the reflux period, NMP (20 mL), DMPU (2 mL), and NaH (Aldrich, dry, 100 mg, 4.07 mmol) were added. The resulting mixture was stirred at 150

°C for 72 h. The reaction was cooled to room temp., and partitioned between water (50 mL) and EtOAc (100 mL). The aqueous layer was extracted with EtOAc (100 mL) and the combined organics washed with water (2 x 50 mL), dried (Na2SO4), and

concentrated to about 3g of material. The brown oil was chromatographed on silica (200 mL, 4 cm diam. column), to obtain N-(3-amino-l,3,5,(10)-estratrien-17-one-yl)-2- hydroxy-2-methylpropionamide as an off-white solid (770 mg, 2.17 mmol, 58.6% yield).

mp 159-160 °C. Η NMR (400 MHz, CDC1 ₃ ) δ 8.60 (br s, 1 H, N-H), 7.44 (d, 1 H, C ₄ -

H, J = 1.99 Hz), 7.27-7.21(om's, 2 H, C,-H and C ₂ -H), 2.90 (dd, 2 H, C ₆ -H, J = 9.1 1,

4.27 Hz), 2.56-1.93 (om's, 8 H), 1.70-1.40 (om's, 6 H), 1.54 (s, 6 H, C(CH ₃ ) ₂ ), 0.90 (s, 3

H, C ₁₈ -CH ₃ ); ¹³ C NMR (100 MHz, CDCl ₃ ) 5 221.0, 174.1, 137.3, 135.9, 135.3, 125.8,

199.9, 117.1 , 74.2, 50.4, 48.0, 44.1, 38.2, 35.8, 31.5, 29.5, 27.9, 26.4, 25.7, 21.6, 13.8; IR (KBr pellet) 1686 (C=0 stretch), 1724 (C=O stretch), 3387 (NH stretch), 3430 (OH stretch); MS (CI/NH3) 373.

Example 3

Preparation of N-(2-naphthyl)-2-hydroxy-2-methylpropionamide.

To a solution of 2-naphthol (533 mg, 3.70 mmol) in dioxane (20 mL) was added NaH (Aldrich, dry, 300 mg, 12.2 mmol) and CS2CO3 (4.00 g, 12.2 mmol). The resulting

mixture was stirred at room temperature for about 30 minutes, then 2-bromo-2-methyl- propanamide (2.03 g, 12.2 mmol) was added and the resulting mixture was stirred at

reflux for 16 h. After the reflux period, NMP (20 mL), DMPU (2 mL), and NaH (Aldrich, dry, 100 mg, 4.07 mmol) were added. The resulting mixture was stirred at 150

°C for 72 h. The reaction was cooled to room temp., and partitioned between water (50

mL) and EtOAc ( 100 mL). The aqueous layer was extracted with EtOAc (100 mL) and

the combined organics washed with water (2 x 50 mL), dried (Na2SO4), and

concentrated to about 3 g of material. The brown oil was chromatographed on silica (200 mL, 4 cm diam. column), eluting with 3:7 EtOAc/hexane to obtain N-(2-naphthyl)-2- hydroxy-2-methylpropionamide as a white solid (607 mg, 2.65 mmol, 71.6% yield).: mp

155-157 °C. Η NMR (300 MHz, DMSO) δ 9.74 (br s, 1 H, N-H), 8.41 (d, 1 H, C,-H, J

= 2.20 Hz), 7.86-7.76(om's, 4 H), 7.49-7.37 (om's, 2 H), 5.80 (br s, 1 H, O-H), 1.40 (s, 6

H, C(CH ₃ ) ₂ ); ¹³ C NMR (75 MHz, DMSO) δ 175.7, 136.2, 133.3, 129.8, 128.1 , 127.4,

127.3, 126.3, 124.6, 120.6, 1 15.6, 72.5, 27.7; IR (KBr pellet) 1607, 1634, 1655 (amide

C=O stretches), 3289 (NH/OH stretch); MS (CI/NH3) 247; Analysis: Calculated C 73.34 H 6.59 N 6.1 1 Found C 72.97 H 6.57 N 5.89.

Example 4

Preparation of N-(2-dibenzofuranyI)-2-hydroxy-2-methylpropionarnide To a solution of 2-hydroxydibenzofuran (682 mg, 3.70 mmol) in dioxane (20 mL) was added NaH (Aldrich, dry, 300 mg, 12.2 mmol) and CS2CO3 (4.00 g, 12.2

mmol). The resulting mixture was stirred at room temperature for about 30 minutes, then 2-bromo-2-methyl-propanamide (2.03 g, 12.2 mmol) was added and the resulting mixture was stirred at reflux for 18 h. After the reflux period, NMP (20 mL), DMPU (2

mL), and NaH (Aldrich, dry. 100 mg, 4.07 mmol) were added. The resulting mixture

was stirred at 150 °C for 72 h. The reaction was cooled to room temp., and partitioned between water (50 mL) and EtOAc (100 mL). The aqueous layer was extracted with EtOAc (100 mL) and the combined organics washed with water (2 x 50 mL), dried (Na2SO4), and concentrated to about 3 g of material. The brown oil was

chromatographed on silica (200 mL, 4 cm diam. column), eluting with 3:7 EtOAc/hexane

to obtain N-(2-dibenzofuranyl)-2-hydroxy-2-methylpropionamide as an off-white solid (580 mg, 2.15 mmol, 58.1% yield). This was recrystallized from toluene for an analytical

sample: mp 134- 137 °C. 1H NMR (300 MHz, CDC1 ₃ ) δ 8.83 (br s, 1 H, N-H), 8.41 (d,

1 H, C,-H, J = 2.34 Hz), 7.92 (m, 1 H, Ar-H), 7.56-7.29 (om's, 5 H, Ar-H), 2.46 (br s, 1

H, O-H), 1.60 (s, 6 H, C(CH ₃ ) ₂ ); ^, C NMR (75 MHz, CDC1 ₃ ) δ 174.2, 156.8, 152.9,

132.8, 127.3, 124.6, 124.2, 122.7, 120.8, 1 19.5, 1 12.0, 11 1.7, 74.3, 28.0; IR (KBr pellet) 1651, 1668 (amide C=0 stretches), 3364 (NH stretch), 3383 (OH stretch); MS (El) 269; Analysis: Calculated C 71.36 H 5.61 N 5.20 Found C 71.43 H 5.58 N 5.06.

Example 5

Preparation of 3-amino-l,3,5(10)-estratrien-17-ol and N-(3-amino-l,3,5,(10)- estratrien-17-ol-yl)-2-hydroxy-2-methyIpropionamide

To a solution of b-estradiol (1.00 g, 3.67 mmol) in dioxane (20 mL) was added NaH (Aldrich, dry, 400 mg, 16.7 mmol) and CS2CO3 (4.00 g, 12.2 mmol). The resulting

mixture was stirred at room temperature for about 30 minutes, then 2-bromo-2-methyl- propanamide (2.03 g, 12.2 mmol) was added and the resulting mixture was stirred at

reflux for 16 h. After the reflux period, NMP (20 mL), DMPU (2 mL), and NaH (Aldrich, dry, 100 mg, 4.07 mmol) were added. The resulting mixture was stirred at 150

°C for 72 h. The reaction was cooled to room temp., and partitioned between water (50

mL) and EtOAc (100 mL). The aqueous layer was extracted with EtOAc (100 mL) and

the combined organics washed with water (2 x 50 mL), dried (Na2SO4), and

concentrated to about 3g of material. The brown oil was chromatographed on silica (200 mL, 4 cm diam. column), eluting with 3:7 EtOAc/hexane to obtain first the starting estradiol (120 mg, 12% recovery) and then 3-amino-l,3,5(10)-estratrien-17-ol as an off-

5 white solid (100 mg, 0.368 mmol, 10% yield).: mp 75-77 °C; Η NMR (300 MHz,

DMSO) δ 6.90 (d, 1 H, C H, J = 8.2 Hz), 6.33 (dd, 1 H, C ₂ -H, J = 8.2, 2.5 Hz), 6.25 (d,

C ₄ -H, J = 2.5 Hz), 4.70 (br s, 2 H, NH ₂ ), 4.47 (d, 1 H, C ₁₇ -H, J = 4.9 Hz), 3.55-3.47 (m, 1 H), 2.68-2.62 (m, 2 H, C ₆ -H), 2.23-1.72 (om's, 5 H), 1.62- 1.52 (m, 1 H), 1.42-1.03

(om's, 7 H), 0.66 (s, 3 H, C, ₈ -CH ₃ ); ^I3 C NMR (75 MHz, DMSO) δ 145.9, 136.2, 127.6,

10 125.5, 113.9, 11 1.9, 80.0, 49.5, 43.6, 42.8, 36.6, 29.9, 29.2, 27.1, 26.1, 22.8, 1 1.3; IR (KBr pellet) 3430 (NH/OH stretch); MS (El) 271.

A column flush with EtOAc (700 ml) afforded the N-(3-amino-l,3,5,(10)-estratrien-17- ol-yl)-2-hydroxy-2-methylpropionamide as a brownish semi-solid (300 mg, 0.839 mmol, 15 22.8% yield). This was recrystallized from toluene to obtain an off-white powder: mp

175-177 °C. Η NMR (400 MHz, CDC1 ₃ + few drops DMSO) δ 8.73 (br s, 1 H, N-H),

7.35-7.15 (om's, 3 H, Ar-H), 4.49 (br s, 1 H, O-H), 3.65 (t, 1 H, C ₁₇ -H, J = 8.9 Hz),

2.81-2.76 (m, 2 H, C ₆ -H), 2.34-1.78 (om's, 6 H), 1.66-1.08 (om's, 8 H), 1.44 (s, 6 H,

C(CH ₃ ) ₂ ), 0.71 (s, 3 H, C, ₈ -CH ₃ ); ^{l 3} C NMR (100 MHz, CDC1 ₃ + few drops DMSO) δ

0 174.9, 137.2, 136.1, 135.2, 125.6, 119.6, 1 16.8, 81.4, 73.4, 49.9, 44.0, 43.0, 38.5, 36.6,

30.2, 29.5, 27.6, 27.0, 26.0, 22.9, 1 1.0; IR (KBr pellet) 1665 (C=O stretch), 3322 (NH

stretch), 3376 (OH stretch); MS (El) 357.

Example 6 Preparation of N-(4-ethoxyphenyl)-2-hydroxy-2-methylpropionamide.

To a solution of 4-ethoxyphenol (51 1 mg, 3.70 mmol) in dioxane (20 mL) was

added NaH (Aldrich, dry, 300 mg, 12.2 mmol) and CS2CO3 (4.00 g, 12.2 mmol). The

resulting mixture was stirred at room temperature for about 30 minutes, then 2-bromo-2- methyl-propanamide (2.03 g, 12.2 mmol) was added and the resulting mixture was

stirred at reflux for 16 h. After the reflux period, NMP (20 mL), DMPU (2 mL), and

NaH (Aldrich, dry, 100 mg, 4.07 mmol) were added. The resulting mixture was stirred at

150 °C for 72 h. The reaction was cooled to room temp., and partitioned between water

(50 mL) and EtOAc (100 mL). The aqueous layer was extracted with EtOAc (100 mL) and the combined organics washed with water (2 x 50 mL), dried (Na2SO4), and

concentrated to about 2 g of material. The brown oil was chromatographed on silica (200

mL, 4 cm diam. column), eluting with 3:7 EtOAc/hexane to obtain N-(4-ethoxyphenyl)- 2-hydroxy-2-methylpropionamide as an off-white solid (536 mg, 2.40 mmol, 64.8%

yield).: mp 146-148 °C. Η NMR (400 MHz, CDC1 ₃ ) δ 8.59 (br s, 1 H, N-H), 7.45 (dd,

2 H, Ar-H, 7 = 9.0, 2.2 Hz), 6.84 (dd, 2 H, Ar-H, 7 = 9.0, 2.2 Hz), 4.00 (q, 2 H, CH ₂ -

CH ₃ , 7 = 7.1 Hz), 2.73 (br s, 1 H, O-H), 1.53 (s, 6 H, C(CH ₃ ) ₂ ), 1.39 (t, 3 H, CH ₂ -CH ₃ ,

7 = 7.1 Hz) ; ^π C NMR (75 MHz, CDC1 ₃ ) δ 174.0, 155.7, 130.6, 74.0, 63.7, 27.9, 14.8;

IR (KBr pellet) 1604, 1647 (amide C=0 stretches), 3256 (NH stretch), 3281 (OH

stretch); MS (CI CH4) 224; Analysis: Calculated C 64.55 H 7.67 N 6.27 Found C 64.16

H 7.47 N 6.07.