Arthur G. Schultz and Victoria Kanel

I I Photochemical Preparation of Indoles Cornell University Ithaca. NY 14853 I An organic chemistry experiment

The chemical literature is filled with a variety of organic laboratory photoreactions, which provide novel heterocycles, molecules of theoretical interest, and pharmaceutically valuable, naturally occurring materials. In industry, perhaps the most impressive photochemical process to date is the ~hotooximation of cvclohexane, which ~ roduces c-ca~rolac-

what is Guly remarkable i s that the photoreaction proceeds with a quantum yield of less than unity and the product sells for $1-$2/kg.

Despite these documented achievements, a search through the manv nonular oreanic laboratorv textbooks reveals that a t best, ashgle phot&hemical expercment is included. Almost without exce~tion. the exoeriment involves the sunlieht ini- tiated photorkdudion of henzophenone to benzophenof While the experiment is certainly convenient, it, unfortunately, demonstrates little of the synthetic value of modern organic photochemistry.

We have modified a research-oriented photochemical ex- periment in order to provide an early exposure to the synthetic advantages of organic photochemistry (2) . The experiment has been designed for undergraduate organic laboratory stu- dents with minimal expertise in laboratory operations. Fnr- thermore, a mechanistically interesting carbon-carbon bond forming reaction is exemplified.

Discussion The reaction sequence to be studied is outlined in the equation shown. Two equivalents of N-methylaniline2 and

The indole nucleus is found in a of Oc- ethyl-2-chloroacetoacetate2 react at steambath temperature curring alkaloids which have profound pharmacologic effects to give the 2-anilinoacetoacetate which exists as the tau. (3). A few of the more well-known indole alkaloids are lysergic mixture and Ib, Using proton nmr and ir analysis, acid, yohimbine, and reserpine. In nature, the indole portion it can be shown that the enolic form I is favored in solution of the alkaloid is derived from the amino acid tryptophan. The (CDC13, -95% I b ) , Purification of I extraction methods student may he familiar with the important Fischer indole gives a lightly colored oil suitable for the photochemical part synthesis, which has been used in the laboratory synthesis of of the experiment. countless indole and indole alkaloid systems. Many useful, hut Irradiation of I in ethanol solution is accomplished with an less well-known methods are available, and recently we ex- ordinary 275 and the reaction may be carried to tended the me tho do lo^ to include a photochemical synthesis near completion in one week The conversion of I to an (2). indole involves the completely stereoselective photocycliza-

tion-rearrangement of 1 b to the 3-hydroxyindole 2 followed ' Undergraduate research participant, Come11 University, %mmer by the acid.catalyzed dehydration of 2 to give 3. Although the 1978. Available from Aldrich Chemical Company, Incorporated. intermediate 2 is never detected in this experiment, by using

Q ml graduated cylinder is used conveniently to measure the a high intensity ultraviolet light source and an inert solvent amounts of chemicals to be used. This operation is best performed such as n-Pentane, be obtained as an unstable in an exhaust hood. oil in quantitative yield (2) . Indole 3 is isolated by removing

Volume 56, Number 8. August 1979 1 555

a portion of the ethanol solvent (distillation a t atmospheric pressure) and crystallization from the remaining ethanol in about 4060% overall yield from the ethyl-2-chloroacetoace- tate.

We suggest tha t a portion of one laboratory period he used t o set-uo the first reaction. which is allowed t o ~ r o c e e d on a s t eamhkh overnight. ~ m h e d i a t e l ~ before the'start of the followine dav's laboratorv oeriod. the student removes his " " . flask from the steamhath, stopper* it, and stores i t until his next lahoratorv oeriod. Durine the first full laboratorv meeting, the s t i d e k will isolate &e 2-anilinoacetoacetate and prepare for the photoreaction. During the next full laboratory period one week later, the student will distill a portion of the ethanol from his photoreaction mixture, purify the indole hy crystallization and obtain a melting point for his product. If time is available, the purity of the indole could be examined by thin layer ~hrorna io~raphic (tlc) analysis.

Experimental

Preparation of Ethyl-2-(Kmethylanilino)-acetoacetate ( 1). A mixture of ethyl-2-ehloroaeetoacetate2 (4.3 ml, 0.021 male, Ia-

~hrymator)~ and N-methylanilinez (6.4 ml, 0.062 mole) in a round- bottomed flask is heated on a steamhath for 24 hr. After cooline. the contents of the flask is transferred with the aid of ether t o n 2 k ml

Photochemical Cyclization of lb; Preparation of Ethyld- methyl-(N-methylindole)-2-carboxylate (3).

A portion of the 2-anilinoacetoacetate 1 (-2 g) is placed in a 50 ml Erlenmeyer flask. Ethanol is added until the 50 ml mark is reached and nitrogen gas is passed through the solution for about 10min. The flask is stoppered immediately with aserum cap4 and tightly sealed with wire drawn around the folded side of the stopper sleeve. The flask is inverted and placed in a beaker for support. Irradiation is carried out with a 275 W sunlamp, the surface of which is positioned about 8 in. from the nearest surface of the Erlenmeyer flask. CAUTION: a light shield is recommended and the area around the lamp should be open to prevent an excessive build-up of heat. Several reaction vessels may be positioned under one lamp and after irra- diation for one week <5% of the starting material remains (proton nmr analysis). The photoreaction mixture is transferred to a distillation apparatus, and ethanol is distilled using a flame until about 10-15 ml of solution remains in the distillation flask. Upon cooline. crvstalli- zation occurs, and the product is collected by suction filtra&n. A wash with cold ethanol (1-2 ml) and air dryinggives indole 3; a second crop of crystals may be taken (mp 76-77°C; 40-50% overall yield from ethyl-2-ehloroacetoacetate).

Acknowledgment

This work was supported by the National Institutes of Health. We thank William K. Hagmann for providing technical assistance during the development of this experiment.5

water (2 X 30 ml) and dried over anhydrous magnesium sulfate. After Literature cited filtration of the drying agent, the solution is transferred to a distil- lation assembly, and the ether is removed by heating the distillation ( 1 ) S l d t h , Jacques, "Photochemistry as s T m l in ~eterocyele ~ y n t h ~ ~ i ~ : ~ ~ t ~ ~ ~ ~ ~ ~ ~ ~ ~ .

6, 2021 (19771. flask on a steamhath. The remaining oil (-5 g) is of sufficient purity (21 schult,, ~ ~ t h ~ ~ G. and H ~ ~ ~ ~ ~ ~ , willism ~ . , . . ~ ~ t o ~ ~ t ~ ~ - d i r e e t e d ~ h ~ t o ~ ~ l a t i ~ ~ : for the photoreaction. Synthesis of Indoks and 8-Hydmxyindolinea: Chem. Cammun., 726 (1976).

(8) J. E. Sarton."The lndoleAlkaloids/in"TheAIkaloids: (Editor: Manske. R. H. F.), VII, Academic Press, New York. 1960.

R e d sleeve type available from Arthur H. Thomas Company; 16 (4 Many excellent booksdealing with the theory andprecticeofo~aniephatachemistry X 25, No. 8753-D72. are available: far example, we T U I ~ , N. J., " ~ o l e e u l ~ r ~ h ~ t ~ ~ h ~ ~ i ~ t ~ ~ : ~ ~ ~ j ~ ~ i ~ ,

Address correspondence to A. G. S. at the Department of Chem- W. A., Inc., New York, 1961; Calvert, J. G.. and Pitts, J. N., Photochemistry, John Wiley and Sons, Inc.. New York, 1966: Cowan, D. 0.. and Drisko, R. L., Elsmsnrs a{

istry, Rensselaer Polytechnic Institute, Tray, New York 12181. Oraanic ~hotochamistry, plenum P Z ~ S . ~ e w ~ o r k . 1976.

556 1 Journal of Chemical Education