188 J . Org. Chem., Vol. 43, No. 2, 1978 (2)
Vedejs, Engler, and Telschow
S.Masamune, G. S. Bates. and P. E. Georghiou, J. Am. Chem. SOC., 96, 3686 (1974).
( 3 ) M. F. Semmelhack and R. D. Stauffer, J. Org. Chem., 40, 3619 (1975). (4) E. C. Ashby, T. F. Korenowski, and R. D. Schwartz, J. Chem. SOC.,Chem. Comrnun. 157 (1974). (5) E. C. Ashby, and J. J. Watkins, J. Org. Chem., 42, 1099 (1977). (7) E. C. Ashby and J. J. Lin, J. Org. Chem. (in press). (8) E. C. Ashby and A. B.Goel, Inorg. Chem. (in press). (9) E. C. Ashby, J. J. Lin, and R. Kovar, J. Org. Chem., 41, 1939 (1976). (10) E. C. Ashby and J. 6.Boone, J. Org. Chem., 41, 2890 (1976).
(11) E. C. AshbyandR. D. Schwartz, J. Chem. Ed., 51, 65 (1974). (12) D. F. Shriver, "The Manipulation of Air Sensitive Compounds", McGraw-Hill, New York, N.Y., 1969. (13) G. B. Kauffman and L. A. Teter, Inorg. Synth., 7, 9 (1963). (14) H. 0. House and P. D. Weeks, J. Am. Chem. SOC.,97, 2770 (1975). (15) R. Herrmann and C. T. J. Alkemade, "Chemical Analysis by Flame Photometry", Vol. 14, 2nd ed, Wiley, New York, N.Y., 1963. (16) F. P. Treadwell and W. T. Hall, "Analytic Chemistry", Vol. 11, 9th ed in english. Wiley, New York, N.Y., 1948, p 650. (17) T. J. Murphy and J. K. Taylor, Anal. Chem., 37 929 (1965).
Transition-Metal Peroxide Reactions. Synthesis of a-Hydroxycarbonyl Compounds from Enolates E. Vedejs,* D. A. Engler, and J. E. Telschow Department of Chemistry, University of Wisconsin, Madison, Wisconsin 53706 Received June I O , 1977 Enolates of ketones, esters, and lactones are oxidized by MoOyPyHMPA (MoOPH) to give a-hydroxy derivatives. The reaction succeeds with carbonyl compounds having a-methylene or a-methine groups, but enolates from methyl ketones give variable results. The hydroxylation process does not afford products of oxidative C-C cleavage which might be formed from an a-hydroperoxycarbonyl intermediate. If the initial intermediate from an enolate and MoOPH is heated, further oxidation to an a-dicarbonyl compound occurs in poor yield. These results suggest an intermediate having the partial structure R'C(=O)RCHOMo04Lz-. Hydroxylation of kinetic enolates derived from unsymmetrical cyclic ketones, cyclohexenones, and certain methyl ketones can be achieved. Acyloin regioisomers are not interconverted under the reaction conditions. Hydroxylation of relatively nonhindered ketones is complicated by aldol condensation between unreacted enolate and the oxidation intermediate. This problem can be minimized by working in dilute solution or by using an inverse addition technique (enolate added to MoOPH). Oxidation of enolate analogues prepared from oximes or N,N-dimethylhydrazones has been demonstrated, although yields are low. Stabilized enolates of 1,3-dicarbonyl compounds are not hydroxylated using the typical procedure, and the related dianions afford complex product mixtures.
Introduction The synthetic problem of enolate hydroxylation has been the object of numerous s t ~ d i e s . ~ Barton , ~ , ~ - ~and co-workers achieved the direct enolate oxygenation of pregnan-20-one, and subsequent hydroperoxide reduction gave the 17a-hydroxy derivative.1a Gardner et al. found that modified conditions using in situ triethyl phosphite reduction of the hydroperoxides gave superior yields.2a,b In the absence of phosphite, oxidative a-carbon cleavage may occur (eq 1, Scheme I), a reaction which has been studied in several analogous system^.^ The Barton oxidation cannot be used to introduce a hydroxyl group at an enolizable methyl or methylene group because a second fragmentation pathway (eq 2, Scheme I
Scheme I) is available to the resulting a-hydroperoxy ketones4 An a-dicarbonyl compound is formed initially, but further oxidation is facile and complex product mixtures are obtained. Practical oxygenation of carboxylate dianions can be achieved in a number of examples without in situ peroxide reduction by triethyl p h o ~ p h i t eThe . ~ carboxylate dianion is apparently sufficiently reactive to attack the peroxide 0-0 bond so that peroxide does not accumulate as oxygen is introduced. If the dianion is added to excess oxygen, the hydroperoxide can be isolated in moderate yield.5ac Oxidation of amide or lactam enolates by the inverse addition method is also feasible.6 The same technique can be employed for hydroxylation of a-branched esters,6az7 but esters having an a-methylene group behave ~ n p r e d i c t a b l y . ~ ~ ~ ~ ~ A promising method for synthesis of a-hydroxy derivatives of unbranched carbonyl compounds involves the epoxidation of enol silanes8 An a-trimethylsiloxycarbonylcompound can be isolated under nonhydroxylic conditions, and facile hydrolysis to the free alcohol is possible. Acetoxylation of enols with reagents such as mercuric acetate or lead tetraacetate might also be considered: but hydrolysis of a-acetoxy derivatives of ketones is often complicated by interconversion of acyloin regioisomers as will be shown later in this account. A preliminary reportlo from our laboratory described the direct hydroxylation of enolates with the molybdenum peroxide reagent Mo05.pyridine-HMPA (MoOPH).ll Representative ketone and ester enolates were reacted with MoOPH in tetrahydrofuran solution, and hydrolysis of the product gave a-hydroxycarbonyl compounds. The details of the oxidation procedure are the subject of this paper.
0 1978 American Chemical Society oo22-a2~~/78/194~-0188$01,00/0
J . Org. Chem., Vol. 43, No. 2, 1978 189
Transition Metal Per'oxide Reactions Scheme I1
0C.H-
1
3
I
A
MCPSA
bH 2
/
J
5
MCPBA
6
Our interest in enolate hydroxylation began as part of a synthetic project which required conversion of a model ester 1 into the a-hydrox:y ester 2. Small-scale attempts to hydroxylate the enolate with molecular oxygen were not promising, so we examined the oxidation of the derived ketene acetal 3. The reaction of 3 with Pb(OAc)4 (1:lstoichiometry, T H F , 0 "C) gave at least three products, and an NMR spectrum of the crude mixture showed only traces of olefinic hydrogens remaining. This reaction was not investigated further. Oxidation with MCPBA did afford some of the desired a-trimethylsiloxy ester 5 (50-60%), but ca. 10% of the cleavage product 7 was inevitably present as we11.12 Since formation of ketone 7 can be explained by epoxidation of 3 and subsequent nucleophilic opening of 4 by a second mole of MCPBA as shown in Scheme ][I, we turned to the presumably nonnucleophilic epoxidizing agent M o O ~ ~ H M P A Treatment .~~ of 3 with 1mol of MoOE,.HMPAin methylene chloride a t 20 "C resulted in an exothermic reaction, and aqueous workup gave 2 in good yield. An obvious simplification of the oxidation procedure is to avoid the silylation step and to oxidize the enolate directly. Although this is possible with MOO~SHMPA, the reagent is hygroscopic and must be dried thoroughly before use. A more convenient reagent for enolate hydroxylation proved to be the highly crystalline and reasonably air-stable complex Moo5. pyridine-HMPA (MoOPH).ll This substance reacts with typical enolates in the temperature range -70 to -20 "C, and aqueous workup affords a-hydroxycarbonyl compounds. Properties of MoOgPyHMPA (MoOPH). Mimoun et al. have described the isolation of crystalline molybdenum peroxides having a variety of ligands." A solution of H2MozOll is prepared by dissolving Moo3 in 30% Hz02 a t 40
"C, and addition of HMPA to this solution affords crystalline MoO~.H~O-HMPA in high yield. This operation can be performed routinely by the published method on a 50-g scale, provided that rigorous internal temperature control is maintained during dissolution of Moo3 (see Experimental Section). Mimoun et al. converted the sparingly soluble Mo05-H20. HMPA directly into MoOPH by treatment with pyridine. We prefer to first prepare Mo05-HMPA1l from the hydrate (vacuum desiccator). The anhydrous peroxide is easily soluble in tetrahydrofuran (THF) and addition of one equivalent of pyridine precipitates MoOPH as finely divided crystalline material. In our hands, Mimoun's procedure gave MoOPH contaminated with hydrate, and purification of the product by recrystallization failed because MoOPH decomposes slowly in solution at 25 "C or above. All of the molybdenum peroxides are light sensitive and decompose to a significant extent after several days of (improper) storage in a clear glass container at room temperature. However, these reagents can be stored for months with no apparent decomposition in a refrigerator shielded from light. We have observed no indication that molybdenum peroxides are shock-sensitive or in any way hazardous in contact with typical organic solvents. Upon heating, small samples of MoOPH decompose with copious gas evolution. Larger samples (0.1-1 g) ignite when placed on a hot plate but do not detonate. We are aware of one instance where a sample of MoOs-HMPA decomposed with sufficient force to break the jar and char the contents after several weeks of storage at ambient temperature without protection from light.I4 Our experience indicates that no such hazards exist with MOOS. PyeHMPA (MoOPH) if the reagent is refrigerated between use. Nevertheless, routine precautions are appropriate when handling this high molecular weight peroxide. Molybdenum peroxides behave as electrophilic oxygen donors and resemble organic peracids in some of their chemical properties. Anionic species such as alkyllithium reagents15 or nitrile-stabilized carbanions16 are attacked rapidly by MoOyHMPA or by MoOPH a t temperatures below 0 "C, resulting in C-0 bond formation. Electron-rich neutral substrates including sulfides,I7N-silylamides,18or oximes1: are oxidized more slowly and ambient temperatures are typically necessary. Alkenes can also be oxidized, but temperatures between 40 and 80 O C are usually employed for catalytic epoxidation (Mo catalyst ROOH)I9or for stoichiometric epoxidation with Mo05.HMPA.l3 Enolate Hydroxylation with MoOPH. The procedure for hydroxylation of carbonyl compounds consists simply of adding the ketone or ester to a 5-10% excess of lithium diisopropylamide in THF-hexane at -70 "C, followed by addition of crystalline MoOPH at a temperature between -70 and -20 "C depending on the individual case. As soon as the sparingly soluble reagent has dissolved, the reaction can be quenched with aqueous sodium sulfite and extracted to recover products. Sodium sulfite apparently reduces unreacted Movl species, produces water-soluble salts, and facilitates recovery of organic products. A simple water workup can also be used, but this typically affords emulsions, lower material balance, and highly colored organic-soluble molybdenum-containing side products. Two reaction pathways can be written for enolate oxidation with MoOPH which are consistent with the known tendency of MOOS chelates to transfer one of the peroxidic oxygens rather than the oxo oxygen to potential n ~ c l e o p h i 1 e s .The l~~ first (path a, Scheme 111)involves cleavage of the 0-0 bond and formation of 8, while the second (path b) cleaves an 0-Mo bond to give 9. If path b is the preferred mechanism, then one might expect to isolate a-hydroperoxycarbonyl compounds or their a-carbon cleavage products (Scheme 1, eq 1).Since no such products have been detected from any MoOPH hy-
+
190
J . Org. Chem., Vol. 43, No. 2, 1978
Vedejs, Engler, and Telschow
Table I. MoOPH Oxidation of Esters and Lactonesd
101-97-3 106-73-0 2021-28-5 42858-39-9 19340-56-8 21303-80-0 a
a-Hydroxy ester
Ester
Registry no.
Ethyl phenylacetate Methyl heptanoate Methyl 3-phenylpropionate Ethyl bicyclo[2.2.2]oct-2-ene-5-carboxylate a-Butylbutyrolactone y-Phenyl-y-methylbutyrolactone
Yield
Ethyl mandelate 58%" Methyl 2-hydroxyheptanoate 74%'3 Ethyl 2-hydroxy-3-phenylpropionate 60%O! Ethyl 5-hydroxybicyclo[2.2.2]oct-2-ene-5-carboxylate85%'3,c a-Hydroxy-a-butylbutyrolactone 73%b a-Hydroxy-y -phenyl-y -methylbutyrolactone 56%"
Isolated yield. b GLPC yield. Mixture of exo and endo isomers. All oxidations done at -78 "C, 2 h; 1.1mmol of MoOPH added 1.05 mmol of LDA in THF-hexane.
t o enolate from 1 mmol of ester
+
Table 11. Oxidation of Ketones* Registry no. 1009-14-9
4 51-40-1 611-70-1 529-34-0 76-22-2 4528-68-1 1444-65-1
Ketone
Oxidation temp, "C
Valerophenone
-220 -4 40 -44
Deoxybenzoin Isobutyrophenone &-Tetralone Camphor
-22
4,4-Diphenylcyclohexanone
2-Phenylcyclohexanone
-22 -22 -22; heat to 60 "C, 16 h -2 2 -44
64070-08-2
-22
19637-35-5
-4 4
THPO
@-Hydroxyketone 60% 70% 62% 34% 6 5%C 48% 70% (endo OH)d 44%e
-2 2
dP
46% 70% (4:1, 19a-19b)
&-Diketone 13% 11%
< 2%
26% -
b
< 2% 11% b
< 5% b
75% (160 0H)g
b
UInverse addition method, enolate added to MoOPH. b Yield of a-diketone not established. cFor NMR data, see ref 20. See ref 31 for characterization of all four possible isomers. e Mixture of diastereomers, stereochemistry not determined. f B . M. Trost, M. Preckel, and L. M. Leichter, J. A m . Chem. SOC.,97, 2224 (1975). gRemoval of OTHP at pH 3 gave 3P,16a-dihydroxyandrost-5-en-l7-one: A. Hassner and P. Catsoulacos, J. Org. Chem., 31, 3149 (1966); K. Fotherby, A. Colas, S. Atherden, and G. Marrian, Biochem. J., 66, 664 (1957). h All oxidations performed by addition of 1.5 mmol of MoOPH to enolate from 1 mmol of ketone + 1.05 mmol of LDA unless noted otherwise, THF-hexane solution. Yields refer to pure material isolated by preparative layer chromatography. d
Scheme 111
0 II
0-O-MoO,L,-
I
9
droxylation, path a is considered more plausible. Table I lists typical ester or lactone hydroxylations performed by addition of MoOPH to the enolate a t -78 "C. All esters studied were oxidized within 2 h a t -78 "C, and no attempt was made to optimize individual cases. By comparison, ketone enolates (Table 11) are less reactive. The representative procedure consists of MoOPH addition to the enolate a t -22 "C, followed by Na2S03 quenching as soon as the reagent has dissolved (2-5 min). However, results were more reproducible a t -44 "C for several of the ketones examined. In general, ketone hydroxylations are more sensitive to reaction conditions, and it is advisable to optimize temperature, concentration, and stoichiometry variables to minimize side reactions. We have examined the hydroxylation of valerophenone in
some detail because this system is especially prone to side reactions under typical conditions (-22 "C, 1.05 m LDA, 1.5 mol of MoOPH, 15 min). Although the a-hydroxy ketone 1120 is still formed in reasonable yield (60%),the product mixture also contains a-diketone 1221(13%),recovered valerophenone (5%), and two unstable compounds which could not be obtained in pure form. After several hours a t room temperature, the unstable products decompose to a new substance (14) (22% based on valerophenone) which is assigned the furan structure from N3MRdata and the absence of carbonyl or hydroxyl absorptions in the infrared spectrum. If the experiment is repeated using 1mol of MoOPH/2 mol of enolate, the yield of 14 increases (42%) a t the expense of 11 (43%) and a-diketone 12 ( comparison of NMR spectra with authentic material. T h e furan 14 was obtained as a colorless oil which darkened slowly upon exposure to oxygen: 'H NMR (CDC13, 6) 7.6 ( 2 H , d , J = 8 Hz), 7.1-7.5 (8H . m). 2.6 (4 H. br t. J = 7 Hz), 1.2-1.8 (4 H , m ) , 0.95 (3 H , t. J = 7 Hz).0.82 ( 3 H . t. ./ = 7 HZJ: I3C NMR (CDC13,6) 151, 146.3, 133.9. 132. 129.6. 128.2, 128, 126.5, 126.2, 125.1, 124.3, 121.6, 28.3, 26.2, 22.9. 21.8. 13.9. 13.6: IR (neat. cm-') 2960 (s),2930 (sj, 2870 ( s ) , 1595 (in),I495 (si. 1130 ( m ) .1070 (m), 990 (m); (no absorptions at
