Reaction of N-Bromosuccinimide with Secondary Alcohols

brine-cooled separatory funnel. The ether solution of free iminoester obtained was then dried with anhydrous sodium sulfate and used for the preparati...
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STUCRWESCH, HAMMER, AND BLAU

methyl p-bromopropionimidate hydrobromide was suspended in 500 ml. of anhydrous ether and cooled to -10". This suspension was then treated in portions with a cold, aqueous solution of potassium carbonate (40%) in a jacketed, brine-cooled separatory funnel. The ether solution of free iminoester obtained was then dried with anhydrous sodium sulfate and used for the preparation of the thionoester without delay. The identity of this iminoester was established by its conversion to the thionoester, as all attempts to eliminate the ether under vacuum led to decomposition. All other iminoesters were prepared in an analogous manner from the corresponding hydrogen halide salts. Methyl 8-chlorothionopropionate. An ether solution of methyl P-chloropropionimidate was prepared from 79 g. (0.5 mole) of methyl p-chloropropionimidate hydrochloride by the general method described, and saturated with hydrogen sulfide. The solution turned yellow, and a white precipitate separated, which was filtered off and washed with ether. It consisted of ammonium hydrogen sulfide and was discarded. The filtrates were combined, dried with sodium sulfate, and distilled under vacuum to yield 42 g. (61%) of a yellow liquid, b.p. 63-65' (13 mm.). Ethyl P-chlorothionopropionate and ethyl p-bromothionopropionate were prepared in an analogous manner from the corresponding propionimidates. In Table I1 analyses and boiling points are listed. Reaction of acrylyl chloride with sodium sulfhydrate. Anhydrous sodium sulfhydrate (62 g., 1.1 moles), prepared from sodium ethoxide and hydrogen sulfide in alcoholic solution and separated by addition of ether, was suspended in 250 ml. of ether, and 90 g. (1.0 mole) of acrylyl chloride was added gradually, stirring and cooling continuously. The temperature was kept below 20". Stirring was continued for 1 lw. after the end of the reaction, and the solid precipitate obtained was separated from the ether solution by filtration.

[CONTRIBUTION FROM

THB

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The latter was discarded, as it was found to contain only traces of material. Treating of a part of the yellow solid obtained with dilute hydrochloric acid, followed by ether extraction did not yield any ether soluble material. The main portion was extracted repeatedly with water to dissolve inorganic salts. An ashfree residue remained after filtration and drying, which was extracted successively with hot methanol, benzene, andtoluene. Much remained undissolved. Cooling of the solutions yielded white powders, which were analyzed. Starting with 10 g. of dried crude material, extraction with boiling benzene yielded 3 g. of purified product. Anal. Calcd. for C3H40S(thioacrylic acid): C, 40.9; H, 4.57; SI 36.3. Found: C, 41.0; H, 4.90; S, 35.2. Molecular weights (Rast) and melting points were determined for the different fractions separated from solvents: Mol. Wt. 316 m.p. 87-88" Methanol extract: Mol. Wt. 542 m.p. 118-120" Toluene extract: Mol. Wt. 698 m. p. Benzene extract: (insoluble) m.p. 130-135" Residue: Methacrylyl chloride and sodium su2fhydrate. Methacrylyl chloride (52 g., 0.5 mole) was reacted with 34 g. (0.6 mole) of sodium sulfhydrate in 250 ml. of ether a t room temperature. The resulting material was separated into a salt residue and an ether solution, which contained the organic part of the reaction products. After evaporation of the ether, a yellow semisolid material was obtained, which solidified on standing. Soluble in ether and benzene when freshly prepared, it became partly insoluble after 1 to 2 days. The residue remaining after extraction with benzene was analyzed: Anal. Calcd. for CdHoOS (thiomethacrylic acid): C, 47.1; H, 5.93; S, 31.4. Found: C, 46.9; H, 5.91; S, 30.2. LINTHICUM, MD.

CHEMICAL LABORATORIES OF THE UNIVERSITY OF WICHITAAND O F TEiE VETERANS ADMINISTRATION, WICHITA, KANSAS]

THE

RESEARCH LABORATORY

Reaction of N-Bromosuccinimide with Secondary Alcohols C. G. STUCKWISCH, GARY G. HAMMERlljZ

AND

N. F. BLAU

Received June 1.4, 1967 When aliphatic secondary alcohols are oxidized with N-bromosuccinimide under anhydrous conditions, subsequent bromination occurs via debromination of N-bromosuccinimide by hydrogen bromide, followed by bromination of the ketone by free bromine This bromination can be suppressed by addition of a proton acceptor such as Pyridine or calcium carbonate.

Kruse et al.' attempted to oxidize ethyl lactate to ethyl pyruvate, they obtained a mixture of ethyl pyruvate and ethyl bromopyruvate from equimolecular quantities of N-bromosuccinimide and ethyl lactate, whereas twice the quantity of N-bromosuccinimide gave a 64y0 yield of ethyl bromopyruvste. The latter result was obtained with several other (1) Abstracted in part from the Master's Thesis of Gary secondary alcohols. Ethyl mandelate was oxidized G. Hammer, University of Wichita. to ethyl phenylglyoxylate in satisfactory yields. (2) Present address: Department of Chemistry, Georgia Our interest in the preparation of a-ketoesters Institute of Technology, Atlanta, Ga. and their halogenated derivatives prompted us to (3) L. F. Fieser and S. Rajagopalan, J . Am. Chem. SOC., investigate the mode of formation of a-brominated 71, 3935 (1949); 71, 3938 (1949). (4) M. Z. Barakat and G. M. Mousa, J. Pharm. Pharma- ketones from secondary aliphatic alcohols, with a col., 4, 115 (1952). view to finding a method for repressing the bromiN-bromosuccinimide has been used as an oxidizing agent for the conversion of secondary aliphatic alcohols to the corresponding ketone^.^^^ N-bromosuccinimide6 and N-chlorosuccinimide6 have been shown to react with the aromatic secondary alcohol, benzhydrol, to give benzophenone. When

(5) M. Z. Barakat, M. F. A. El-Wahab, and M. M. El-Sadr, J. Am. Chem. SOC.,77, 1670 (1955). (6) Hebbelynck and R. M. Martin, Experientia, 5, 69 (1949).

(7) P. F. Kruse, N. Geurkink, and K. L. Grist, J. Am. Chem. SOC.,76, 5796 (1954).

DECEMBER

1957

REACTION OF N-BROMOSUCCINIMIDE WITH SECONDARY ALCOHOLS

nation reaction. We visualized two possible routes t o the brominated ketones:

lH+

RCH, HR

(CHnCO),NBr + 0

I.

RCH%R

+ (CH2C0)2NH + HBr

(1)

0

& + (CH2CO)eNBr BrO

RCHz R

4

II

RAHCR

+ ( C H a C O ) , ~ H (2)

OH RCHhHR

+ (CH2C0i2NBr--+ 0

+ (CH2CO)zNH+ HBr

(1)

+ HBr + (CH&O),NH + Brp

(2)

RCE&&R

11. (CHzCO)2NBr

0

RCHp&R

+ Brz +R

Ketones have been brominated alpha to the carbonyl function with N-bromosuccinimide in the absence of both light and peroxides.8We were unable to brominate either ethyl pyruvate or acetone with N-bromosuccinimide in refluxing carbon tetrachloride. On the other hand, 2-propanol, like ethyl lactate, yields a brominated ketone when reacted with N-bromosuccinimide. Barakat and Mousa4 did not report the formation of bromoacetone in the latter reaction. Their results are not necessarily at variance with ours since they used a ten-to-ane molar ratio of 2-propanol to N-bromosuccinimide. The following evidence is offered in support of route 11. Ethyl bromopyruvate was obtained in 40% yield from equimolar amounts of ethyl pyruvate and N-bromosuccinimide in the presence of HBr. A mixture of ethyl mandelate, N-bromosuccinimide and ethyl pyruvate gave ethyl phenylglyoxylate (89yo), and ethyl bromopyruvate (55%) : HO

0 I1 CaH&H-6OCpH5

I

+ BrN( COCHP)~+ 0 0

Cab-

k-i ! O C Z H +~ HN(COCHZ)Z+ HBr

followed by reactions I1 (2) and I1 (3). Preferential reaction of pyridine or calcium carbonate with the hydrogen bromide liberated in the oxidation sup(8) H. Schmid and P. Karrer, Helv. Chim. Acta, 29, 573 (1946). For additional references see, C. Djerassi, Chem. Revs., 43, 271 (1948). Djerassi points out that the claim for the bromination of the methyl ketone group in 3-pentene2-one and mesityl oxide by NBS [N. P. Buu-Hoi, E x p e r i a t i a , 2, 310 (194611 is equivocal since the possibility of allylic rearrangement was not considered in the purported evidence for the structure of the brominated products. Furthermore, Southwick, J . Am. C h . Sac., 72, 1600 (1950), has shown that benaalacetone is not brominated in the methyl group by NBS.

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presses or eliminates the production of brominated ketones. Bromine vapor, present in copious amounts in the upper part of the reaction flask and lower part of the reflux condenser when a proton acceptor is absent, still persists, though to a lesser extent when calcium carbonate is present. Pyridine eliminates the bromine vapor. From Table I it can be seen that pyridine is more effective than calcium carbonate in preventing bromination. However, in the case of ethyl lactate better yields of ethyl pyruvate are obtained with calcium carbonate as a proton acceptor. Pyridine or pyridinium bromide apparently catalyzes the formation of high boiling non-brominated products. The reaction appears to be general for secondary alcohols, provided the alcohol contains no functional groups that are sensitive to N-bromosuccinimide. For example, p-hydroxyisovaleronitrile yields a variety of products when reacted with N-bromosuccinimide despite the presence of a proton acceptor. It is of interest t o note that the oxidation of ethyl 3-chlorolactate to ethyl chloropyruvate with N-bromosuccinimide is not accompanied by bromination, though not admixed with pyridine or calcium carbonate. EXPERIMENTAL

Attempted bromination of ethyl pyruvate with N-bromosuccinimide. A mixture of 5.8 g. (0.05 mole) of ethyl pyruvate, 8.9 g. (0.05 mole) of N-bromosuccinimide, and 75 ml. of carbon tetrachloride was refluxed for 48 hr. Filtration and distillation of the a t r a t e yielded an 85% recovery of unreacted ethyl pyruvate. Bromination of ethyl pyruvate wath N-bronwsuccinimide and hydrogen bromide. Hydrogen bromide was slowly bubbled through a refluxing mixture of 5.8 g. (0.05 mole) of ethyl pyruvate, 8.9 g. (0.05 mole) of N-bromosuccinimide, and 75 ml. of dry carbon tetrachloride until the reddish brown bromine color disappeared (16 hr.). The mixture was filtered and the filtrate was dried over anhydrous sodium sulfate and distilled. The yield of ethyl bromopyruvate was 4.8 g. (40%) b.p. 71-73' (5 mm.), ny 1.464. Bromination of ethyl pyruvate with N-bromo,wccinimide in the presence of ethyl mandelate. A mixture of 4.64 g. (0.04 mole) of ethyl pyruvate, 7.21 g. (0.04 mole) of ethyl mandelate, 7.21 g. (0.04 mole) of N-bromosuccinimide, and 75 ml. of dry carbon tetrachloride was refluxed for 10 hr. The succinimide was filtered off and the filtrate was dried over sodium sulfate and distilled a t 5 mm. There was obtained 0.53 g. (10%) of unreacted ethyl pyruvate (b.p. 51-53', n'," 1.403), 3.9 g. (55%) of ethyl bromopyruvate (b.p. 7173O), and 6.3 g. (89%) of ethyl phenylglyoxylate (b.p. 1081120). Synthesis of ethyl pyruvate from ethyl lactate and N-bromoswcinimide. To a solution of 10 g. (0.084 mole) of ethyl lactate in 75 ml. of dry carbon tetrachloride were added 14.24 g. (0.08 mole) of N-bromosuccinimide and 8.4 g. of calcium carbonate. After four hours refluxing, the mixture was filtered, the filtrate dried over anhydrous sodium sulfate and fractionated. The yield of ethyl pyruvate wa8 5.67 g. (58%) and ethyl bromopyruvate, 2.57 g. (19%). In another experiment calcium carbonate was replaced by an equivalent amount of pyridine and the reaction mixture was held between 60 and 70" for 4 hr. The carbon tetrachloride was decanted and the residue washed with dry carbon tetrachloride. After removal of the carbon tetra-

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22

TAl3LE I REACTION OF N-BROMOSUCCINIMIDE WITH VARIOUS SECONDARY ALCOHOLS'

Alcohol

Moles of Alcohol: Moles of NBSb

%Propanol %Propanol 2-Propanol Cyclohexanol Phenyl methyl carbinole Phenyl methyl carbinol Ethyl lactate Ethyl lactate Ethyl lactate Ethyl 2-hydroxybutyratee

1: 1 1:1 1: 1 1:1 1:1 1:2 li:1 1:I 1:1 1:1

Proton Acceptor None CaCOs Pyridine Pyridine Pyridine None None CaCOa Pyridine Pyridine

Products Ketone

%

None AcetoneC Trace Acetone 60 Cyclohexanone 61 Acetophenone 65 None Ethyl pyruvate 10 Ethyl pyruvate 58 Ethyl pyruvate 42 Ethyl 2-ketobutyratel 50

Brominated ketone

%

Bromoacetone Bromoacetone None Noned None Phenacyl bromide Ethyl bromopyruvate Ethyl bromopyruvate None None

30 30

45 20 19

a Carbon tetrachloride was the solvent in all reactions. When pyridine was used as the proton acceptor the temperature was held between 60-70"; the reactions with 2-propanol are exothermic; the others were refluxed from 4-8 hr. N-Bromosuccinimide. Isolated as the 2,4-dinitrophenylhydrazone; m.p. 126'. H. Schmid and P. Karrers reported the direct bromination of cyclohexanone with N-bromosuccinimide. The oxidation in this case is extremely rapid. e Ref. 7. B.p. 66-67" (16 nim.); m.p. of phenylhydrazone 191'. Van der Sleen, G., Rec. trav. chim., 21, 234 (1902).

chloride on a steam bath the residue was diiuted with ether, washed successively with saturated aqueous calcium chloride and 5% hydrochloric acid, dried over anhydrous magnesium sulfate, and fractionated. The yield of ethyl pyruvate was 42%. No ethyl bromopyruvate was formed. Oxidation OJ cyclohexanol. A mixture of 5 g. (0.05 mole) of cyclohexanol, 8.9 g. (0.05 mole) of N-bromosuccinimide, and 3.9 g. (0.05 mole) of pyridine in 50 ml. of dry carbon tetrachloride waF heated on a steam bath a t 60-70" for 4 hr. The mixture was allowed to stand overnight at room temperature, filtered, and the filtrate fractionated through a short column. The yield of cyclohexanone, b.p. 148-150°, was 3 g. or 617'. The melting point of its 2,4dinitrophenylhydrazone was 162'. Oxadation of ethyl S-chlorolactate. A mixture of 7.67 g. (0.05 mole) of ethyl 3-chlorolactate, 8.9 g. (0.05 mole) of Noromosuccinimide, and 75 ml. of carbon tetrachloride was rrfiuxed for 3 hr The mixture was filtered, the filtrate dried over anhydrous sodium sulfate, and distilled. The yield of

ethyl chloropyruvate0 boiling a t 74-75" (8 mm.) was 5.5 g. (72%). Attempted oxidation of 0-hydroxyisovaleronitrilc. A mixture of 9.9 g. (0.1 mole) of P-hydroxyisovaleronitrile, 17.8 g. (0.1 mole) of N-bromosuccinimide, 7.9 g. (0.1 mole) of pyridine in 100 ml. of carbon tetrachloride reacted spontaneously as evidenced by the rise in temperature of the reaction mixture. After the initial temperature increase had abated the mixture was kept at 60 to 70" for 2 hr. The mixture was then treated as described for ethyl lactate. Distillation yielded isobutyraldehyde, a small amount of 2-oxo-iso-valeric acid and a larger fraction which, judged by its boiling point (217-218"), may have been the dimer of p-oxoisovaleronitrile descrbed by Moritz.lo WICHITAI4$KAN (9) J. Parrod, Compt. rend., 218, 599 (1944). (10) E. Moritz, J. Chem. SOC.,39, 23 (1881).

[SOKTRIBUTION FROX THE SHELLDEVELOPMENT C0.j

ydrogen Peroxide. 11. A Novel Use of Selenium Dioxide as Catalyst for the Ring Contraction of Cycloalkanones to Cyelsallaanecarboxylic Acids' GEORGE B. PAYKE

AND

CURTIS W. SMITH

Recerued J u n e 10, 1957 Oxic!sti\le ring a n t r a c t i o n s u f cyeloHel;)tanone,cyclohexanone, and cyciopentanone to cyclohexane-. cyc1opentane.- and. eyclobntanecarboxj I;" n!,irit . iii 3 4 . 3 . and 23% yieids, respactwely, have been obtained with hydrogen peroxide and selenium dicixia.: a b catalyst

might unaergo the well-known reactron with seleilium &oxide giving alpha-dikelones, with hyarsgen peroxide serving merely to oxidize seleniunr metal back tc the dioxide. It was found, however, t,hat aiong wit)ii other competing rearticrib. a!i ~'nreek+ tones iinderwent oxidative ring contractlor to e)-clohe::ane-, cyclopentane- ana ~ j i c ! o S u t a ~ ~ ~ i l ~ r OGXY!K acia" ,n a;, 32, and 23% yields, resppcdi3rely. A d i p ~acid ~ P afi idemiSec as another Y > * > ~ C -