synthesis of 2-substituted 5-acetyl-1(h)-imidazoles via 3-chloro-4,4-dimethoxy-2-butanone and...

3494 J. Org. Chem. 1984,49, 3494-3498

Synthesis of 2-Substituted 5-Acetyl-1 (H)-imidazoles via 3-Chloro-4,4-dimethoxy-2-butanone and Related 3,4-Disubstituted

3-Buten-2-ones

Lawrence A. Reiter Central Research Division, Pfizer, Inc., Groton, Connecticut 06340

Received February 27, 1984

A variety of 3,4-disubstituted 3-buten-2-ones have been synthesized and reacted with acetamidine to yield 5-acetyl-2-methyl-l(H)-imidazole, 5-substituted pyrimidines, or both. The nature of the producta depends on the substituents at positions 3 and 4 of the butenone. With relatively poor leaving groups at position 3, pyrimidines are generated exclusively, while with a good leaving group at position 3 and a group at position 4 which is not easily eliminated, 4acetylimidazolea are formed predominantly. Convenient large-scale syntheses of the highly functionalized compounds, 3,4dichloro-3-buten-2-one and 3-chlorc~4,4dimethosy-2-butanone, have been developed, and the utility of the latter compound for the synthesis of 2-substituted 5-acetyl-l(H)-imidazoles has been demonstrated.

Interest in the pharmacology of histamine and histidine has led to the development of various synthetic routes to substituted imidazoles; however, few of these can be ap- plied to the synthesis of 5-acetyl-2-alkyl-l(H)-imidazoles. Recent work in these laboratories addressing this problem has yielded two syntheses of such compounds.'t2 For various reasons, however, neither of these was well suited to scale up. The problems associated with Lipinski's method in which an amidine is condensed with 3-bromo- 4-ethoxy-3-buten-2-one (1)2 lay in the preparation of the butenone and not in the cyclization itself. As a result we focused on synthesizing 1 or a synthetic equivalent by a reliable and safe method. Since the bromo and ethoxy groups of 1 serve only as leaving groups during the cyclization, the former presumably being ejected through displacement and the latter by elimination during aro- matization, replacement of these two substituents by functionally similar groups should yield butenones capable of cyclizing to imidazoles upon treatment with amidines.

Our initial synthetic endeavors toward the synthesis of these 3,4-disubstituted 3-buten-2-ones involved utilizing a substituted propanone in which said substituent would be a potential leaving group and which would furthermore activate the propanone to "formylation" type reactions (eq 1). Of such possible propanone derivatives: those with

an a-sulfur substituent appeared to have potential since an a-sulfide or a-sulfone would certainly facilitate formylation reactions, and examples exist wherein sulfides4 and sulfones6 have apparently been displaced in intramolecular nucleophilic reactions.

While the a-sulfur-substituted acetones reacted readily with dimethylformamide dimethyl acetal as expected: subsequent treatment of the resulting butenones with acetamidine led only to pyrimidines (Scheme I). The

(1) LaMattha, J. L.; Suleski, R. T.; Taylor, R. L. J. Org. Chem. 1988, 48,897.

(2) Lipinski, C. A.; Blizniak, T. E.; Craig, R. H. J. Org. Chem. 1984, 49, 566.

(3) Some related early experimenta utilizing chloroacetone and di- m e t h y l f o d d e dimethyl acetal indicated that a propanone derivative more stable than chloroacetone would be required: Lipinski, C. A.; Blizniak, T. E., unpubliihed work.

(4) Cohen, T.; Daniewski, W. M. Tetrahedron Lett. 1978, 2991. (5) Parker, W. L.; Woodward, R. B. J. Org. Chem. 1969, 34, 3085.

Julia, M.; Guy-Roualt, A. Bull. SOC. Chim. Fr. 1967, 1411. (6) Abdulla, R. F. Tetrahedron 1979, 35, 1675.

0022-326318411949-3494$01.50/0

Scheme I

2a, X = S0,Ph; Y = NMe, b, X = SPh; Y = NMe, c, X = SO,CH,; Y = NMe, d, X = SCH,; Y = NMe, e, X = S(CH3);I-; Y = NMe, f , X = S(CH,),'BF,-; Y = NMe, g, X = SCH,; Y = OEt h, X = S(CH,),+BF,-; Y = OEt

Scheme I1

3a, X = S0,Ph b, X = SPh c, X = SO,CH, d, X = SCH,

/- I pyrimidine

I imidazole

initial Michael adduct of acetamidine to the butenone did not cyclize to the imidazole because either the sulfonyl and sulfide groups were not sufficiently good leaving groups or elimination of the dimethylamino g r o p occurred faster than five-member ring cyclization (Scheme 11, Y = NMe2). The sulfonium salts 2e and 2f although' containing a much better leaving group a t position 3, preferentially deme- thylated under the reaction conditions, thus reverting to 2d and ultimately cyclizing to pyrimidine 3d. The more electrophilic enol ether 2h behaved similarly.

These results suggested that a better leaving group was needed at position 3 of the butenone; however, any further increase in the leaving capacity of this group was likely to lead to problems during "formylation" of the requisite propanone. As a result, we turned our attention to an alternative butenone synthesis involving Friedel-Crafts chemistry.

In order to prepare the desired 3,4-disubstituted 3-buten-2-ones by a Friedel-Crafts reaction, the union of an

0 1984 American Chemical Societv I , , -

%-Substituted 5-Acetyl-l(H)-imidazoles via 3,4-Disubstituted 3-Buten-2-ones J. Org. Chem., Vol. 49, No. 19, 1984 3495

Scheme I11

"ZC03 cH%cl

CI R.T.

CI "zO

4 (75%)

Table I"

~~~~~

yield of yield of-

X % byproduct, % material, %

yield of 2,a-dimethyl- recovered imidazole, pyrimidine starting

c1 (4) 10 35, Y = C1 none detected b (54 75 5, Y = c1 13 OCHS (5b) 62 2, Y = C1 none detected SCHa ( 5 ~ ) 28 21, Y = CHSS 32 SC(CHS):, (54 13 none isolated 69 N(CHzCHa)z (Se) 2 6, Y = C1 86

"All reactions were run on a 10-mmol scale with a 1.5 molar excess of acetamidine acetate in refluxing dioxane for 24 h except the reaction of 5b which was run at 80 OC. The products and recovered starting materials were isolated by flash chromatography. Starting material was 3-chloro-4,4-dimethoxy-2-butanone which is

slowly converted during the reaction to 5b.

acetyl halide with a dihaloolefin would be required. Al- though the reactions of acyl halides and olefins are known,' there are only two reports in which the olefin is a 1,2-di- haloethylene!pg The first of these describes the reaction of chloroacety1 chloride with 1,Zdichloroethylene and the subaequent dehydrohalogenation with aqueous base to give the unsaturated ketone. With this precedent we expected the reaction of acetyl chloride and 1,2-&chloroethylene to provide a viable precursor to acetylimidazoles.

Accordingly, treatment of acetyl chloride with a slight ex- of aluminum chloride in excess dichloroethylene led to the expected trichloroethyl ketone, which was not pu- rified but treated directly with 10% aqueous sodium carbonate to give 3,4-dichloro-3-buten-2-one (4)'O in 75% distilled yield (Scheme III). The crucial ring-forming step was then attempted by treating 4 with acetamidine. This reaction led to two products, the desired 5-acetyl-2- methyl-l(H)-imidazole and 5-chlor0-2~4-dimethylpyrimidine in 10% and 35% isolated yields, respectively, constrasting sharply with the reaction of 1 with acetamidine which gave the same imidazole and no significant side products.2

Compound 4 was therefore not a synthetic equivalent to 1, and we reasoned that the difference between the two compounds was attributable either to chloride being a poorer leaving group than bromide or to rapid elimination of the &substituent (see Scheme 11, Y = Cl). We were unable to directly test the former hypothesis by preparing the bromo analogue of 4 since dibromoethylene polymer- izes under Friedel-Crafts reaction conditions. However,

(7) Nenitzescu, C. D.; Balaban, A. T. In 'Friedel-Crafts and Related Reactions"; Olah, G. A., Ed.; Interscience: New York, 1963; Vol. 111, Chapter 37, pp 1033-1132.

(8) Catch, J. R.; Elliot, D. F.; Hey, D. H.; Jonea, E. R. H. J. Chem. SOC. 1948,278.

(9) McLamore, W. M.; P'An, S. Y.; Bavley, A. J. Org. Chem. 1966,20, 109.

(10) Compound 5 was synthesized earlier by a circuitous route, see: Petrov, A. A. J. Gen. Chem. USSR 1943,13,165; Chem. Abstr. 1944,38, 1467'.

replacement of the 4-chloro substituent of 4 with other less readily eliminated groups was readily achieved and a series of derivatives of 4 was prepared (see Table I). While initial cyclization experiments indicated that the dimethoxy derivative 5a was clearly the reactant of choice, a direct comparison of these derivatives was provided by treating each with acetamidine under a standard set of conditions and isolating the products by chromatography. The results of these reactions are shown in Table I. Although 4 and 5b were completely consumed within 24 h, the mass bal- ance on these reactions was relatively low due to decom- position. Compound 5c gave imidazole but also led to a simificant proportion of 5-(methylthio)pyrimidine (3d), possibly via an intramolecular rearrangement of the initial Michael adduct (eq 2). Compounds 5d and 5e react very

3d c~ayNicH, ____) - H

slowly, presumably for steric and electronic reasons, respectively. The diethoxy analogue of 5a (not shown in Table I) provided a result comparable to that of 5a.

In comparing the results of 4 and 5b we conclude that the leaving capacity of the substituent at position 4 plays an important role in the reaction course. In contrast, comparison of the reactions of 1 and 5b indicates that the differing leaving capacities of bromine and chlorine do not affect the reaction outcome significantly.

With 5a identified as a viable precursor to 5-acetyl-2- alkyl-1(H)-imidazoles we exploited this chemistry for the large-scale synthesis of these compounds. The Friedel- Crafts acetylation of 1,2-dichloroethylene was run four times on a &mol scale, giving an average yield of 76.5% (range 74.5-79.2%) and conversion of 4 to 5a by treatment with excess sodium methoxide in methanol gave, in three runs of 4-5 mol each, an average yield of 75.1% (range 72.2-78.8%). Reaction of 5a with amidines proceeded well on a large scale; however, in the case of acetamidine, which yields 5-acetyl-2-methyl-1 (H)-imidazole, some problems were encountered because the product partitions poorly between water and organic solvents. As a result, on a 0.5-mol scale only a 46% yield of this imidazole was obtained. More lipophilic imidazoles were easily separated from salts and byproducts by a standard aqueous workup. For example, after such workup 5-acetyl-2-hexyl-l(H)- imidazole was obtained in 68% yield, and the 2-phenyl derivative in 60% yield.

In conclusion, we have described the synthesis of a variety of 3,4-disubstituted 3-buten-2-ones and efforts to convert these to acetylimidazoles. The successful synthesis of such imidazoles depends crucially upon the presence of a good leaving group at position 3 of the butenone and a group which does not readily eliminate at position 4. 3- Chloro-4,4-dimethoxy-2-butanone (5a) was identified as a particularly useful intermediate for the synthesis of acetylimidazoles. In addition, the syntheses described for 5a and 3,4-dichloro-3-buten-2-one (4) make these compounds readily available for use in other synthetic endeavors such as the synthesis of other heterocycles or, in the case of 4, in Diels-Alder reactions or Robinson-type annelations.

3496 J. Org. Chem., Vol. 49, No. 19, 1984

Experimental Section

'H NMR and 13C NMR spectra were recorded on Varian T-60 and Bruker WM-250 spectrometers, respectively. Chemical shifta from tetramethylsiie are reported on the 6 scale. Low-resolution mass spectra were obtained on a Finnigan EI-CI mass spectrometer and exact masses were determined on an A.E.L-MS30 spectrometer. Melting points are uncorrected and were obtained in open capillaries on a Thomas-Hoover melting point apparatus. Elemental anal- were performed by the Analytical Department of Pfiir, Inc. Solvents and reagents were commercially available and used directly unless otherwise indicated. 4-(Dimethylamino)-3-(phenylsulfonyl)-3-buten-2-one (2a).

l-(Phenylsulfonyl)-2-propanone (1.98 g, 10.0 mmol) and dimethylformamide dimethyl acetal (1.43 g, 12 mmol) were combined in THF (50 mL) and stirred at room temperature for 18 h. The solvent was then removed in vacuo and the residue triturated with hexane to give 2.48 g (98%) of pale yellow solid. Recrystallization from ethyl acetate/ hexane gave thick colorless needles: mp 92-94 OC; 'H NMR (CDC13) 6 2.20 (3 H, s), 3.10 (6 H, br s), 7.48 (3 H, m), 7.85 (3 H, m).

Anal. Calcd for ClzHlSNO3S C, 56.89; H, 5.97; N, 5.53. Found C, 56.63; H, 5.68; N, 5.53. 4-(Dimethylamino)-3-(phenylthio)-3-buten-2-one (2b).

l-(Phenylthio)-2-propanone (1.66 g, 10.0 mmol) and dimethylformamide dimethyl acetal (2.38 g, 20 "01) were refluxed in THF (50 mL) for 18 h. The solvent was then removed in vacuo, and the residue was taken up in ether and washed with 1 N sodium hydroxide solution (3X) and saturated ammonium chloride solution and dried over magnesium sulfate. The filtered extract was then concentrated in vacuo and the resulting oil triturated with hexane to give 1.59 g (72%) of light yellow solid, mp 79-81 "C. Chromatographic purification and recrystallization from hexane gave pale yellow needles: mp 80-82 OC; 'H NMR (CDC13) 6 2.30 (3 H, s), 3.22 (6 H, s), 7.2 (5 H, m), 8.17 (1 H, 8) .

Anal. Cakd for C12H1&'OS C, 65.12; H, 6.83; N, 6.33. Found C, 65.15; H, 6.71; N, 6.44. 4-(Dimethylamino)-3-(methylsulfonyl)-3-buten-2-one (2c).

l-(Methylsulfonyl)-2-propanone (2.72 g, 20.0 mmol) and dimethylformamide dimethyl acetal (2.98 g, 25 mmol) were stirred together in THF (100 mL) for 18 h. The solvent was then removed in vacuo to give a yellow oil which solidified upon standing. Recrystallization from hexane/ethyl acetate gave 1.90 g (50%) of light yellow crystals: mp 71-73O; 'H NMR (CDC13) 6 2.43 (3 H, s), 3.10 (9 H, s), 7.68 (1 H, 8). Anal. Calcd for C7H13N03S C, 43.96, H, 6.85; N, 7.33. Found

C, 44.06; H, 6.55; N, 7.44. 4-(Dimethylamino)-3-(methylthio)-3-buten-2-one (2d).

l-(Methylthio)-2-propanone (10.42 g, 0.10 mol) and dimethylformamide dimethyl acetal (23.83 g, 0.20 mol) were refluxed for 28 h in THF (100 mL). The solvents were removed in vacuo and the residue was distilled to give 10.63 g (67%) of yellow liquid: bp 138-145 "C (10 torr); 'H NMR (CDC13) 6 2.08 (3 H, s), 2.37 (3 H, s), 3.30 (6 H, e), 7.73 (1 H, 8).

Anal. Calcd for C7H13NOS C, 52.79; H, 8.23; N, 8.80. Found C, 52.51; H, 7.98; N, 8.54. Dimethyl[4-(dimethylamino)-2-oxo-3-buten-3-yl]sulfodm

Iodide (2e). 2d (1.59 g, 10.0 "01) was refluxed for 4 h in methyl iodide (20 mL). After standing at room temperature overnight, the reaction mixture was diluted with ether and the solid collected, yielding 2.73 g (91%) of light tan powder: mp 125-126 OC; 'H NMR (MezSO-d6) 6 2.32 (3 H, s), 3.17 (6 H, s), 3.40 (6 H, e), 8.15 (1 H, 8).

Anal. Calcd for C&IIJNOS: C, 31.90, H, 5.36; N, 4.65. Found C, 31.61; H, 5.43; N, 4.53. Dimethyl[4-(dimethylamino)-2-oxo-3-buten-3-yl]sulfodm

Tetrafluoroborate (2f). 2d (3.18 g, 20.0 mmol) and trimethyloxonium tetrafluoroborate (2.96 g, 20.0 mmol) were stirred together in methylene chloride (40 mL) for 2 h. The solvent was then removed in vacuo and the residue trituated with 1:l ether:2-propanol to give a solid which was collected, yielding 4.65 g (89%) of yellow solid. Two recrystallizations from 2-propanol gave fine colorless needles: mp 98-101 OC; 'H NMR (MezSO-ds) 6 2.32 (3 H, s), 3.15 (6 H, s), 3.37 (6 H, s), 8.12 (1 H, 8) .

Anal. Calcd for CsH16BF4NO& C, 36.80; H, 6.18; N, 5.37. Found: C, 36.93; H, 6.11; N, 5.34.

Reiter

4-Et hoxy -3-( met hylthio)-3- buten-2-one (2g). To a solution of sodium ethoxide (from sodium, 1.15 g, 50.0 mmol) in absolute ethanol (50 mL) was added a mixture of 1-(methylthiob2- propanone (5.21 g, 50.0 "01) and ethyl formate (4.07 g, 55 "01) with ice cooling. After 6 h at room temperature the reaction mixture was poured into 0.25 N hydrochloric acid and extracted with ether (5X). The extra& were dried with magnesium sulfate, filtered and concentrated in vacuo to give 2-(methylthio)aceto- acetaldeyde as an orange oil which existed as two isomers of the enol: 'H NMR (CDCl,) minor isomer, major isomer, respectively, 2.08, 2.22 (3 H, 2 s), 2.32, 2.43 (3 H, 2 s), 8.05, 8.52 (1 H, 2 9).

The above crude product was dissolved in a mixture of ethanol (150 mL) and toluene (30 mL) and refluxed with periodic removal of distillate through a Dean-Stark trap. After 3 h the cooled reaction mixture was concentrated in vacuo to a brown oil which was distilled to give 2.51 g (34%) of yellow oil: bp 115-123 "C (7 torr); 'H NMR (CDC13) 6 1.42 (3 H, t, J = 7 Hz), 2.23 (3 H, s) 2.37 (3 H, s), 4.23 (2 H, q, J = 7 Hz), 7.73 (1 H, s).

Anal. Calcd for C7HlzOzS C, 49.29; H, 6.89. Found C, 49.27; H, 7.10. Dimethyl(4-ethoxy-2-oxo-3-buten-3-yl)sulfonium Tetra-

fluoroborate (2h). 2g (731 mg, 5.0 m o l ) and trimethyloxonium tetrafluoroborate (740 mg, 5.0 mmol) were stirred together in methylene chloride for 4 h at room temperature. The solvent was then removed in vacuo to give a brown oil which could not be crystallized. 'H NMR indicated the material to be an equal mixture of two isomers of the desired product, and the material was utilized as is: 'H NMR (MezSO-d6) 6 1.10, 1.42 (3 H, 2 t, J = 7 Hz), 2.05, 2.37 (3 H, 2 s), 2.85, 3.08 (6 H, 2 s), 3.43, 4.57 (2 H, 2 q, J = 7 Hz), 7.85 (1 H, br 8). 2,4-Dimethyl-5-(phenylsulfonyl)pyrimidine (3a). 2a (2.53

g, 10.0 mmol) and acetamidine acetate (1.77 g, 15.0 mmol) were refluxed together in THF (100 mL) for 24 h. The solvent was removed in vacuo, and the residue was dissolved in ether and washed with water (2X) and saturated sodium chloride solution and dried over magnesium sulfate. Concentration of the filtered extract gave a yellow oil which crystallized upon trituration with hexane, yielding 1.98 g (80%) of an off-white solid. Recrystal- lization from hexane/ethyl acetate gave colorless crystals: mp 83-85 "C; m u spectmm, m / e 248 (M+); 'H NMR (CDC13) 6 2.63 (3 H, s), 2.75 (3 H, s), 7.5 (3 H, m), 7.8 (2 H, m), 9.07 (1 H, 8).

Anal. Calcd for C12H12N202S: C, 58.04; H, 4.87; N, 11.28. Found: C, 58.08; H, 4.86; N, 11.18. 2,4-Dimethyl-S-(phenylthio)pyrimidine (3b). 2b (1.59 g,

7.18 mmol), acetamidine acetate (1.77 g, 15.0 mmol), and po- tassium carbonate (2.07 g, 15 "01) were refluxed for 72 h in THF (75 mL). The cooled reaction mixture was diluted with ether (75 mL) and washed with saturated sodium bicarbonate solution and saturated sodium chloride solution and dried over magnesium sulfate. Concentration of the filtered extract gave 1.53 g (98%) of a yellow oil which was essentially pure by 'H NMR. An analytical sample was prepared by flash chromatography: Mass spectrum, m/e 216 (M'); 'H NMR (CDClJ 6 2.50 (3 H, s), 2.68 (3 H, s), 7.22 (5 H, s), 8.38 (1 H, 8).

Anal. Calcd for ClzH12N$: C, 66.63; H, 5.59; N, 12.95. Found C, 66.43; H, 5.74; N,-13.32. 2,4-Dimethyl-5-(methylsulfonyl)pyrimidine (3c). 2c (191

mg, 1.0 mmol) and acetamidine acetate (118 mg, 1.0 mmol) were refluxed in THF (10 mL) for 12 h. The cooled reaction mixture was diluted with ether (25 mL) and washed with saturated sodium bicarbonate solution and saturated ammonium chloride solution and dried over magnesium sulfate. The filtered extract was concentrated in vacuo, giving a colorless solid which was recrystallized from pentane/ether to give 55 mg (29%) of colorless prisms: mp 85-86 "C; mass specrum, m / e 186 (M+); 'H NMR

Anal. Calcd for C7Hl0NZO2S: C, 45.14; H, 5.41; N, 15.05. Found C, 45.13; H, 5.36; N, 15.04. 2,4-Dimethyl-5-(methy1thio)pyrimidine (3d). (A) 2d (1.59

g, 10.0 mmol) and acetamidine acetate (1.77 g, 15.0 mmol) were refluxed in dioxane (100 mL) for 120 h. The cooled reaction mixture was concentrated in vacuo and the residue was dissolved in ether (50 mL) and washed with water (2X) and saturated sodium chloride solution and dried over magnesium sulfate. Concentration of the filtered extract gave 1.04 g (67%) of pale yellow solid. Recrystallization from pentane gave colorless needles:

(CDC13) 6 2.82 (3 H, s), 2.87 (3 H, s), 3.15 (3 H, s), 9.08 (1 H, s).

2-Substituted 5-Acetyl-l(H)-imidazoles via 3,CDisubstituted 3-Buten-2-ones J. Org. Chem., Vol. 49, No. 19, 1984 3497

mp 52-53 "C; mass spectrum, m / e 154 (M+); 'H NMR (CDCI,) 6 2.48 (3 H, s), 2.53 (3 H, s), 2.67 (3 H, a), 8.32 (1 H, e).

Anal. Calcd for C7H1JV#: C, 54.51; H, 6.54, N, 18.27. Found: C, 54.49; H, 6.85; N, 17.91. (B) 2g (146 mg, 1.0 "01) and actamidine (177 mg, 1.5 mmol)

were refluxed in dioxane (10 mL) for 4 h. The cooled reaction mixture was concentrated in vacuo and the residue was dissolved in ethyl acetate, washed with water, and dried over magnesium sulfate. Concentration of the fitered extract gave 123 mg (83%) of a yellow oil which solidified upon standing. This material was identical by TLC and 'H NMR with material produced by method A. 3,4-Dichloro-3-buten-2-one (4). Aluminum chloride (734 g,

5.5 mol) was added to a mixture of acetyl chloride (392 g, 5.0 mol) and 1,2-dichloroethylene (2.42 kg = 1.92 L, 25 mol) keeping the temperature around 25 "C. This mixture was then refluxed for 16 h. The cooled mixture was poured into ice and the organic layer separated. The aqueous layer was extracted with methylene chloride (3 x 500 mL), and the combined organics were filtered through Celite and dried over sodium sulfate. The filtered extract was concentration in vacuo to a black oil, 'H NMR (CDCld 6 2.42 (3 H, s), 4.55 (1 H, d, J = 7 Hz), 6.03 (1 H, d, J c 7 Hz), which was vigorously stirred with sodium carbonate (745 g, 6.0 mmol) in water (2.5 L) for 1.5 h. The solids were then filtered off and washed with methylene chloride. The organic layer of the fitrate was separated and the aqueous layer waa extracted with methylene chloride (2 X 200 mL). After drying with magnesium sulfate, the combined organics were fitered and concentrated in vacuo to give a black oil which was distilled to give 550.3 g (79.2%) of nearly colorless, mildly lachrymatory liquid bp 40-46 "C (8 torr) (lit.lo bp 61.5-62 "C (30 torr)); masa spectrum, m/e 138,140,142 (M+), 123, 125, 127 (M+ -Me); 'H NMR (CDCl,) 2.48 (3 H, e), 7.60 (1 H, 9); '9c NMR (CDCl,) 6 26.7 (CH,), 131.5 (HC=), 135.1 (ClC-), 190.0 ( C 4 ) . 3-Chloro-4,4-dimethoxy-2-butanone (sa). To a solution of

sodium methoxide (305 g, 5.64 mol) in methanol (3.78 L) was added 4 (523 g, 3.76 mol) in a slow stream, keeping the temperature at 0 "C. After 30 min at 0 "C, acetic acid (113 g = 107 mL, 1.88 mol) was added, methanol evaporated in vacuo, and the residue dissolved in isopropyl ether (1.5 L). After washing with water (1 L) and saturated sodium bicarbonate solution (250 mL), the extract was dried with magnesium sulfate. The filtered solution was then concentrated in vacuo and the residue distilled to give 488.4 g (78.0%) of colorless liquid bp 66-75 "C (8 torr); mass spectrum, m / e 135, 137 (M+ - OMe), 75 (CH(OMe)2); 'H NMR (CDC13) 6 2.33 (3 H, s), 3.43, 3.47 (6 H, 2 s), 4.23 (1 H, d, J = 8 Hz), 4.63 (1 H, d, J = 8 Hz); exact mass calcd for C&I11CI03 166.0397, found 166.0420. 3-Chloro-4-methoxy-3-buten-2-one (5b). Sa (3.33 g, 20.0

mmol) and p-toluenesulfonic acid (0.76 g, 4 "01) were refluxed together in benzene (200 mL) with continuous slow removal of distillate in a Dean-Stark trap. After 2 h the cooled dark yellow mixture was washed with saturated sodium bicarbonate solution (2 x 50 mL). The organic layer was dried with magnesium sulfate, decolorized with charcoal, and then filtered and concentrated to 1.83 g (68%) of a dark yellow oil which crystallized upon standing and which was spectrally pure. Since this material decomposed at room temperature with in a few days, it was generally utilized immediately in the next reaction step. Mass spectrum, m / e 134, 136 (M+), 119, 121 (M+ - Me); 'H NMR (CDCl,) 6 2.33 (3 H, s),

(OCH3), 113.0 (ClC=), 157.7 (HC=), 191.5 (C=O). 3-Chloro-4-(methylthio)-3-buten-2-one (5c). 4 (6.95 g, 50.0

mmol) and methyl mercaptan (2.41 g, 50.0 mmol) in ether (50 mL) were treated dropwise with triethyl amine (5.06 g, 50.0 "01). An exotherm ensued and the ether refluxed briefly. After 2 h additional ether was added to facilitate stirring, and after 4 h total the salts were removed by fitration and washed with ether. The filtrate was concentrated in vacuo and the orange residual oil distilled to give 5.37 g (74%) of yellow liquid bp 108-110 "C (10 torr); mass spectrum, m / e 150, 152 (M'), 135, 137 (M+ - Me);

(HC=), 188.1 (C=O).

H, 4.59.

4.00 (3 H, s), 7.57 (1 H, 8 ) ; 13C NMR (CDC13) 6 26.2 (CH,), 62.7

'H NMR (CDClJ 6 2.37 (3 H, s), 2.53 (3 H, s), 7.78 (1 H, 9); "C NMR (CDClS) 6 17.1 (SCH,), 25.6 (CH,), 126.0 (ClC=), 145.3

Anal. Calcd for C&ClOS C, 39.86; H, 4.69. Found C, 39.47;

3-Chloro-4-[ (2-methyl-2-propyl)thio]-3-buten-2-one (5d). 4 (20.85 g, 0.15 mol) and 2-methyl-2-propanethiol(l3.53 g, 0.15 mol) in ether (250 mL) were treated with triethylamine (15.18 g, 0.15 mol) in ether (50 mL) at 5 "C. After complete addition the reaction was refluxed for 6 h and then, after standing at room temperature for 72 h, the reaction mixture was washed with water (3X) and saturated sodium chloride solution, dried over magnesium sulfate, and concentrated in vacuo to a brown oil. This was distilled to give 17.56 g (61%) of light yellow liquid, bp 75 OC (0.1 torr), which crystallized upon standing, mp 72-74 "C: mass spectrum, m/e 192,194 (M+), 136,138 (M+ - ClH8), 121,123 (M+ - CIHs - CH,); 'H NMR (@DC13) 6 1.50 (9 H, s), 2.38 (3 H, s), 7.93 (1 H, 8) .

Anal. Calcd for C&Il3C1OS: C, 49.86; H, 6.80. Found: C, 49.71; H, 6.63. 3-Chloro-4-(diethylamino)-3-buten-2-one (50). 4 (16.82 g,

0.117 mol) in ether (235 mL) was treated dropwise with diethylamine (17.13 g, 0.234 mol) during which an exotherm occurred which briefly refluxed the ether. After 30 min the salts were filtered off and washed with ether. The fitrate was concentrated in vacuo and the residue distilled to give 10.11 g (49%) of pale yellow liquid: bp 80-90 "C (0.1 torr); mass spectrum, m / e 175,

t, J = 7 Hz), 2.27 (3 H, s), 3.50 (4 H, q, J = 7 Hz), 7.48 (1 H, 8) ;

99.8 (ClC=), 143.5 (HC=), 191.0 (C=O). Anal. Calcd for C&ClNO C, 54.70; H, 8.03; N, 7.98. Found:

C, 54.27; H, 7.78; N, 8.16. 3-Chloro-4,4-diethoxy-2-butanone. To a solution of sodium

ethoxide (from sodium, 2.30 g, 0.10 mol) in ethanol (180 mL) was added a solution of 4 (13.90 g, 0.10 mol) in ethanol (20 mL) with cooling. After 2 h acetic acid (4 mL) was added and the salts were removed by filtration. The filtrate was concentrated in vacuo, diluted with ether, filtered to remove further precipitated salts, and concentrated again. The residue was distilled to give 12.49 g (64%) of pale yellow liquid: bp 52 "C (1.5 torr); mass spectrum, m/e 149,151 (M+ - OEt), 103 (CH(OEt)2); 'H NMR (CDC13) 6 1.17, 1.22 (6 H, 2 t, J = 7 Hz), 2.30 (3 H, s), 3.6 (4 H, m), 4.18 (1 H, d, J = 6 Hz), 4.68 (1 H, d, J = 6 Hz). Reaction of 3,4-Dichloro-3-buten-2-one with Acetamidine.

A mixture of 4 (1.36 g, 10.0 mmol), acetamidine hydrochloride (1.43 g, 15.0 mmol), and sodium acetate (2.87 g, 35.0 mmol) was refluxed in dioxane (50 mL) for 24 h. Isolation of the major components by flash chromatography gave 126 mg (10%) of 5acetyl-2-methyl-1(H)-imidazole identical by TLC, MS, 'H NMR, and mp with authentic material' and 496 mg (35%) of 5- chloro-2,4-dimethylpyrimidine1' as an oil: mass spectrum, m/e

(1 H, 8). 5-Acetyl-2-methyl-1(H)-imidazole. A mixture of 5a (83.3

g, 0.50 mol), acetamidine hydrochloride (94.5 g, 1.0 mol), and sodium acetate (123 g, 1.5 mol) was refluxed for 18 h in dioxane (500 mL). After cooling, the mixture was filtered through a silica gel pad which was washed with dioxane until no further product was eluted. The filtrates were concentrated in vacuo to a red oil which was flash chromatographed (100 mm column), yielding 28.8 g (46%) of product. Recrystallization of this from 1:l ethyl acetate/isopropyl ether gave tan crystals, mp 132-133 "C (lit.' mp 127-129 OC). Reaction of 3-Chloro-4-(methylthio)-3-buten-2-one with

Acetamidine. A mixture of 5c (1.51 g, 10.0 mmol), acetamidine hydrochloride (1.43 g, 15.0 mmol), and sodium acetate (2.05 g, 25.0 mmol) was refluxed for 24 h in dioxane (50 mL). After cooling, the mixture was concentrated in vacuo and the residue flash chromatographed to yield 478 mg (32%) recovered butenone starting material, 348 mg (28%) of 5-acetyl-2-methyl-l(H)- imidazole identical by TLC, MS, and 'H NMR with authentic material, and 320 mg (21 %) of 2,4-dimethyl-5-(methylthio)pyrimidine which was identical by TLC, 'H NMR, and mp with the pyrimidine prepared from 2d and which was clearly different by TLC, 'H NMR, and mp from 2,4-dimethyl-6-(methylthio)pyrim- dine.12

177 (M+), 160, 162 (M+ - CH3); 'H NMR (CDCl3) 6 1.27 (6 H,

13C NMR (CDClJ 6 14.6 (CHSCH,), 25.6 (CH,), 47.2 (CH,CH,),

142, 144 (M'); 'H NMR (CDC13) 6 2.57 (3 H, s), 2.67 (3 H, s), 8.43

(11) Busby, R. E.; Khan, M. A.; Khan, M. R.; Parrick, J.; Granville Shaw, C. J.; Iqbal, M. J. Chem. SOC., Perkin Trans. 1 1980, 1427.

(12) Brown, D. J.; Foster, R. V. Aust. J . Chem. 1966, 19, 2321.

3498 J. Org. Chem. 1984,49,3498-3503

5-Acetyl-2-hexyl-l(H)-imidazole. A mixture of 5a (25.0 g, 0.15 mol), heptanimidamide hydrochloride (32.9 g, 0.20 mol), and sodium acetate (28.7 g, 0.35 mol) was refluxed for 6 h in dioxane (500 mL). After cooling, the salts were removed by filtration and the filtrate was concentrated in vacuo to a red oil. This was taken up in ethyl acetate (500 mL) and extracted with 1 N hydrochloric acid (3 X 100 mL). The combined aqueous extracts were washed with ethyl acetate and then carefully basified with sodium carbonate (40 9). This solution was then extracted with chloroform (3 x 100 mL), and the combined extracts were dried over magnesium sulfate. Concentration of the filtered solution gave a light brown solid which was recrystallized from ethyl acetatelhexane to give 12.21 g (42%) light tan solid, mp 105-106 "C. Workup of the mother liquors gave 7.82 g (26%) of oily solid which was pure by TLC but which shbwed some minor imputities by NMR: mass spectrum, m / e 194 (M'); 'H NMR (CDC13) 6 0.8 (3 H, m), 1.3 (6 H, m), 1.7 (2 H, rp), 2.52 (3 H, s), 2.8 (2 H, br t, J = 7 Hz), 7.72 (1 H, 8) .

Anal. Calcd for CllH1&O C, 68.01; H, 9.34; N, 14.42. Found C, 67.84; H, 9.00; N, 14.13. S-Acetyl-2-phepyl-l(H)-imidazole. A mixture of 5a (3.33

g, 20.0 mmole), benzamidine hydrochloride (4.70 g, 30.0 mmol), and sodium acetate (4.10 g, 50.0 mmol) was refluxed for 42 h in dioxane (100 mL). After workup as in the previous example, 3.23 g of crude product was obtained which was recrystallized from cyclohexane/toluene to give 2.33 g (60%) of fine yellow needles, mp 155-157 OC (&,.I3 mp 158-158.5 "C); maas spectrum, m l e 186 (M+), 171 (M+ -.Me); *H NMR (CDC13/Me2SO-d6) 6 2.51 (3 H,

~~

(13) Paul, R.; Menschik, J. US. Patent 4107 307,15 Aug 1978.

s), 7.3 (3 H, m), 7.73 (1 H, s), 8.0 (2 H, m).

C, 70.53; H, 5.43; N, 14.92. Anal. Calcd for CllHl&O C, 70.95; H, 5.41; N, 15.05. Found

Acknowledgment. I thank Professors D. S. Kemp, E. J. Corey, and S. L. Schreiber and my colleagues at Pfizer, especially Drs. J. L. LaMattina and C. A. Lipinski, for their helpful comments and suggestions during both the exec- ution of this work and the preparation of this manuscript.

Registry No. 2a, 91157-81-2; 2b, 76511-78-9; 2c, 91228-03-4; 2d, 91157-82-3; 2e, 91157-83-4; 2f, 91157-85-6; 2g, 91157-86-7; (E)-2h, 91157-90-3; (Z)-2h, 91157-92-5; 3a, 91157-93-6; 3b, 91157-94-7; 3c, 91157-95-8; 3d, 91157-96-9; 4, 91157-97-0; 5a, 91157-98-1; 5b, 91157-99-2; 5c, 91158-00-8; 5d, 91158-01-9; 5e, 91158-02-0; l-(phenylsulfonyl)-2-propanone, 5000-44-2; dimethylformamide dimethyl acetal, 4637-24-5; l-(phenylthio)-2- propanone, 5042-53-5; l-(methylsulfonyl)-2-propanone, 5000-46-4; l-(methylthio)-2-propanone, 14109-72-9; (E)-4-hydroxy-3- (methylthio)-3-buten-2-one, 91157-87-8; (2)-4-hydroxy-3-(methylthio)-3-buten-2-one, 91157-88-9; trimethyloxonium tetrafluoroborate, 420-37-1; acetamidine acetate, 36896-17-0; acetamidine, 143-37-3; 1,2-dichloroethylene, 540-59-0; methyl mercaptan, 74-93-1; 2-methyl-2-propanethiol,75-66-1; diethylamine, 109-89-7; 3-chloro-4,4-diethoxy-2-butanone, 77070-88-3; acetamidine hydrochloride, 12442-5; 5-acetyl-2-methyl-l(H)-imidazole, 78210-66-9; 5-chloro-2,4-dimethylpyrimidine, 75712-73-1; 5- acetyl-2-hexyl-l(H)-imidazole, 91158-03-1; heptanimidamide hydrochloride, 57297-28-6; 5-acetyl-2-phenyl-l(H)-imidazole, 10045-68-8; benzamidine hydrochloride, 1670-14-0.

Mechanism of Copper-Catalyzed Oxygenation of Ketones

L. M. Sayre* and S.-J. Jin Department of Chemistry, Case Western Reserve University, Cleveland, Ohio 44106

Received November 22, 1983

Deoxybenzoin (1) is converted by a Cu(II)-py-E~N-MeOH-02 (py = pyridine) system to a mixture of benzil (2), bidesyl (3), and the cleavage products PhCHO and PhCOOH. A product study comparing reactivities of 1 and 2 under identical conditions established (i) that the conversion of 1 to 3 is effected by Cu(I1) alone, (ii) that PhCHO is generated only from 1, in a reaction that requires both Cu(I1) and 02, and (iii) that 2 undergoes C-C cleavage only in the presence of H20, forming PhCOOH exclusively, in a reaction that requires Cu(I1) but not 02. a-Methyldeoxybemin (5) undergoes an exceptionally slow but similar reaction (giving the tertiary a-keto1 6 rather than diketone 2). Mechanisms for these reactions are presented, and the significance of the results is discussed.

Copper ion catalysis of oxidation and oxygenation reactions is of recognized importance for carrying out se- lective transformations as well as in industrial applica- ti0ns.l There is also much current interest in the mechanisms of such reactions as they relate to model studies aimed at elucidating the biochemical roles of copper in a variety of oxidation and oxygenation cuproenzymes.*

On account of the mechanistic interest and possible synthetic utility, we have initiated a study of the copper-catalyzed oxygenation a to carbonyl groups. The conversion of aliphatic aldehydes to a-keto aldehydes was studied in the middle 1960's by Brackman and Volger, who observed that this conversion was accompanied by C-C bond cleavage, yielding an aldehyde of one less carbon

~~ ~

(1) "Oxidation in Organic Chemistry", Part B; Trahanovsky, W. S., Ed.; Academic Press: New York, 1973.

(2) (a) "Copper Proteins"; Spiro, T. G., Ed.; Wiley: New York, 1981. (b) "Metal Ions in Biological Systems", Sigel, H., Ed.; Marcel Dekker: New York, 1981; Vol. 12 and 13. (c) "Copper Coordination Chemistry: Biochemical & Inorganic Perspectives"; Karlin, K. D., Zubieta, J., Eds.; Adenine Press: Guilderland, NY, 1983.

0022-326318411949-3498$01.50/0

atom, which then underwent further oxygenation and cleavage? These reactions were conducted in MeOH with a cupric salt and excess triethylamine and pyridine. The rationale given for observed cleavage involved a nucleophilic displacement of a carbonyl anion by methoxide (eq 1). Brackman and Volger offered as precedent for such

0 0 0-\ 0 I I

C " ( 1 1 I II 1 1 l3 -MeOCH RCHzCHO - RCCHO _fcB RC-C-H -

MeOH t Ei3N 1 0 2

0

R C - - RCH - etc. I I

displacement the base-promoted C-C cleavage that ac- companies benzil-benzilic acid rearrangements. However,

(3) (a) Volger, H. C.; Brackman, W.; Lemmers, J. W. F. M. Red . Trau. Chim. Pays-Bas 1965,84,1203. (b) Brackman, W.; Gaasbeek, C. J.; Smit, P. J. Ibid. 1966,85,437. (c) Brackman, W.; Volger, H. C. Ibid 1966,85, 446.

0 1984 American Chemical Society

synthesis of 2-substituted 5-acetyl-1(h)-imidazoles via 3-chloro-4,4-dimethoxy-2-butanone and...

Documents