(Hive Bee)
04-16-03 03:26
No 427106
      On tryptophol
(Rated as: excellent)

This is from:

The chemistry of Heterocyclic Compounds - Indoles - Volume 25 part III p180-184 - editor: Houlihan

The 3 volumes on indoles are great, there are plenty of interesting refs in them. I post the synthesis part on tryptophols. Cited References will bee posted tomorrow.


(1). Importance

(a). Tryptophol.

Tryptophol was isolated 666 in 1912 by Ehrlich in nearly quantitative yield from yeast fermentation of tryptophan. It has also been isolated from beer 667a-e and plant seedlings including cucumber 668 and Helianthus669.It is reported to function as a growth regulator in these plants668-670 and probably arises from indoleacetaldehyde669, 671. Tryptophol has been reported as one of the many products formed on uv irradiation of an aqueous solution of tryptophan672.

(b). Other Tryptophols.

5-Hydroxytryptophol, as the glucuronide has been shown to be one of the major metabolites of serotonin in the rat673 and has been detected in carcinoid humans674. The addition of NADH to serotonin-treated rat liver homogenate increases the proportion of 5-hydroxytryptophol relative to combined 5-hydroxyindoleacetaldehyde and 5-hydroxyindole-3-acetic acid675a,b. 5-Hydroxy tryptophol is formed by blood platelets after the release of serotonin mediated by reserpine and thrombin676a,b and is found along with 5-methoxytryptophol in the bovine pineal gland435 and the toad B alvarius414. The latter compound, as well as its O-acetate, has an inhibitory effect on estrus in immature rats similar to melatonin687. Although it is metabolized in the rat, the expected 5-methoxy-6-hydroxyindoleacetic acid has not been found677.
Octahydrotryptophol and its 1-alkyl and 1,2-dialkyl derivatives have been patented as corrosion inhibitors678. Another patent679 covers the synthesis of a series of esters of N-alkyl octahydrotryptophols.

(2). Synthesis

(a). Sodium-alcohol reduction.

In 1930, Jackson reported the first chemical synthesis of tryptophol680, hitherto available only from tryptophan fermentation666, by means of Bouveault-Blanc reduction (Na/EtOH) of the methyl or ethyl esters of indole-3-acetic acid. Yields of 81 % were reported.
In the hands of Hoshino and Shimodaira, 244a,b this procedure gave tryptophol in 46% yield and 5-ethoxy-, 5-methoxy-, and 2-methyl tryptophol in 33, 29, and 32% yield, respectively.
Tacconi has described 681 the preparation of alpha-methyltryptophol and its 5-methoxy derivative in 59% yield by reduction of the corresponding Oxindole derivatives with sodium in refluxing n-propanol. The oxindoles were conveniently obtained by reduction of the isatylideneacetones with sodium borohydride in aqueous ethanol. A one-step lithium aluminum hydride reduction of isatylideneacetone to alpha-methyltryptophol (32%) has recently been reported. 739

(b). Lithium Aluminium Hydride reduction.

1.Acids, Esters, Acid Chlorides

The Bouveault-Blanc reduction has been replaced in modern practice by the lithium aluminum hydride reduction of indole-3-acetic acids or their esters as a high-yield, convenient route to tryptophols. Snyder and Pilgrim, who in 1948 first employed this procedure, reported 682 obtaining tryptophol in 65% yield from indole-3-acetic acid. The methyl 683 and ethyl 684 esters of this acid have been reduced to tryptophol in yields exceeding 90%. 1-Methyl-, 658 2-methyl, 685 and 2-phenyltryptophol 686 have been prepared from the corresponding ethyl indole-3-acetates in yields of 73 and 79% for the methyltryptophols. Taylor has reported 656 , the preparation of the dialcohol, 772, required for the structural elucidation of chinchonamine, by reduction of the diester, 771.
Tryptophols which have been obtained by lithium aluminum hydride reduction of indole-3-acetic acids are 5-benzyloxy- (71%),231,687 5-methoxy- (87%), 687,688 and 5-methoxy-6-benzyloxytryptophol (67%)688; 1-benzyl-, 689 1-benzyl-5-methoxy,329,689 1-benzyl-beta-methyl-, 690 1-benzyl-5-methoxy-beta-methyl, 690 and 1-benzyl-beta-ethyltryptophol689 in yields averaging 80-90%329,689.

Reduction of ethyl indole-3-acetates provided Julia and co-workers with the following tryptophols: 1-benzyl and 1-p-methoxybenzyl derivatives of 5-methoxy- and 5,6-dimethoxytryptophol (79-91%) 329, beta­methyl- and beta,beta-dimethyltryptophol,689 l,beta-dimethyltryptophol689, and 1-benzyl-2,beta-dimethyltryptopho1329.
One of the most convenient procedures for the preparation of tryptophols is that introduced by Elderfield and Fischer, who described691a,b the synthesis of 6-methoxytryptophol in 79% yield by the reduction of 6­methoxyindole-3-glyoxyl chloride with lithium aluminum hydride. This procedure has also been used to obtain 5-benzyloxytryptophol (66%)673 but was reported to be unsatisfactory in the synthesis of 5-methoxy­tryptophol688 and tryptopho1692a itself, although Najer and co-workers72 were successful in obtaining a 78% yield of the latter compound using a slow inverse addition procedure. Nogrady and Dole report692a,b that tryptophol 777 can be obtained in good yield in a procedure claimed to be especially satisfactory for large-scale operations by the simple expedient of converting the glyoxyl chloride 773 to the glyoxylic acid ester 775 before reduction. This procedure was first employed by Speeter and Anthony.248. An 85% overall yield is claimed.692a,b Earlier, Ames and co-workers employed 268 a similar sequence in reducing the tertiary amide 776 to 2-phenyltryptophol 778.

Three different groups have reported the synthesis of 5-hydroxy­tryptophol by the catalytic debenzylation of 5-benzyloxytryptophol, a compound made in turn either by the reduction of 5-benzyloxyindole-3-acetic acid231,687 or by the glyoxylic chloride route above673. Likewise 5-methoxy-6-hydroxytryptophol was prepared by hydrogenolysis of 5-methoxy-6-benzyloxytryptophol688.

2. Ketones

Indole-3-acetone689,693 and its 1-methyl derivative689 have been reduced to alpha-methyltryptophol and its 1-methyl homologue with lithium aluminum hydride.

(C) Synthesis using ethylene oxide and its derivatives.

In 1939, Oddo and Cambieri reported694 the synthesis of tryptophol and of its 2-methyl derivative in 52 and 68% yield, respectively, from the appropriate indole Grignard compound and ethylene oxide. This procedure had been tried earlier by Hoshino and Shimodaira244a,b and somewhat more recently by Snyder and Pilgrim695; however, both groups reported poor yields. A recent patent describes696 the synthesis of alpha-methyltryptophol using propylene oxide and indolemagnesium bromide.
Julia and co-workers have described two routes to tryptophols using ethylene oxides and indole689,690. Tryptophol results in 45% yield from the reaction of indole with ethylene oxide in acetic acid-acetic anhydride followed by saponification of the resulting tryptophol acetate or by the reaction of indole with ethylene oxide in carbon tetrachloride containing stannic chloride. The former procedure has been used to synthesize 5-bromotryptophol697. When the latter procedure was extended to the reaction between indole and either propylene oxide or but-1-ene oxide, mixtures of alpha- and beta-methyltryptophol and alpha- and beta-ethyltryptophol resulted in 58 and 50% yield, respectively.

(d). Miscellaneous syntheses.

Johnson has described698 the synthesis of tryptophol (13% yield), alpha-methyltryptophol, and alpha,(beta-dimethyltryptophol from indole and the appropriate glycol by heating in an autoclave (eq. 27). When glycol monoethyl ethers were employed, tryptophol ethyl ethers resulted.
Grandberg and co-workers achieved the direct synthesis of 2-methyl­tryptophol 780 in a Fischer synthesis with phenylhydrazine and 4-ketopentanol. The intermediate phenylhydrazone 779 was rearranged with cuprous chloride to the tryptophol in 70% yield or with acetyl chloride in dioxane-carbon tetrachloride to its O-acetate in 33% yield699. An analogous synthesis of the N-p-chlorobenzoyl derivative of 2-methyl-5-methoxytryptophol has been reported in a Japanese patent700. 5-Nitrotryptophol results in 5% yield as a by-product of hydrolysis in the Fischer cyclization of gamma-chlorobutyraldehyde p-nitrophenylhydrazone403.
Tryptophol resulted in quantitative yield on reduction of 781 with hydrogen and Raney nickel in ethanol. O-Benzyl tryptophol was produced in 85% yield when sodium borohydride in aqueous pyridine was used in this reduction701.
Szmuszkovicz synthesized alpha,alpha-dimethyltryptophol in 87% yield from ethyl indole-3-acetate and methylmagnesium iodide. The same product resulted in 48% yield when the acyloin 782 was reduced with lithium aluminum hydride in tetrahydrofuran702.
(Hive Bee)
04-16-03 23:46
No 427375
      Preparation of tryptophol
(Rated as: excellent)

Synthesis of tryptophol via yeast reduction of tryptophan:

Ehlrich, F. Ber. Chem. Ges. 45 (1912) 883

Post 9775 (in_outsider: "Tryptophol from Tryptophan via yeast", Tryptamine Chemistry) (German)
Post 10417 (psyloxy: "Re: Tryptophol from Tryptophan via yeast", Tryptamine Chemistry) (English)

Reduction of indole-3-acetic acid ester with Na/alcohol :

from J. Biol. Chem. 88 (1930) p.659-662 :

Methyl and ethyl esters - Both (indole-3-acetic acid) esters were readily secured in practically a quantitative yield in the usual way by refluxing the acid with a considerable excess of the proper absolute alcohol containing a little dry HCl gas, followed by evaporation of the alcohol, washing of the ether solution of the ester with NaHCO3 sol. and with water, drying of the ether solutions with CaCl2, and finally, vacuum distillation. Both esters were distilled in the neighbourhood of 180° at 2mm. of pressure. Neither ester could be induced to crystallize.

Reduction of the ester

Experiment 1.

8.5 gr (0.045 mol) of the methyl ester were reduced in methanol (dried with Na) with the proportions of solvent, sodium, toluene and a mechanical stirrer as directed by Marvel and Tannenbaum1. The yield of crude product, which did not crystallise, amounted to 3.0 gr (0.019 mol). This was converted to the picrate which was recrystallized from hot water and then subjected to alkaline decomposition and ether extraction. The evaporated ether extract was crystallized from dilute alcohol and then from ether-petroleum ether. The pure white crystals melted at 58° (corrected) and exhibited no melting point depression when mixed with a specimen of tryptophol prepared from tryptophan according to Ehrlich's method.

Experiment 2.

It was consequently learned that very good yields of certain dihydric alcohols could be obtained by simply adding dry alcoholic solutions of the esters to the sodium. The experiment described below was performed in similar fashion. Commercial absolute ethanol was treated with sodium sufficient to react with all the water present and then in addition with enough ethyl phtalate to react with all the free alkali remaining in the solution. The alcohol was refluxed for 30 min. and then distilled, to the amount of 250 cc., directly into the flask where the reduction is to be carried out. To this alcohol, 9.15 gr (0.045 mol) of dry ethyl indole acetate were next added, followed by 15 gr. (0.65 mol) of sodium. The flask was attached to a reflux condensor equipped with a CaCl2 tube, and after 30 min., heated for 2 hours on the steam bath. A little remaining sodium was dissipated by the addition of a small amount of 50% alcohol and the product worked up in the costumary fashion. Direct crystallisation from benzene-petroleum ether yielded 4.33 gr melting at 57° (corrected) and 1.30 gr melting at 54-57° (corrected). An additional 0.25 gr was obtained as the picrate. The total of 5.88 gr amounts to a yield of 81% of the theoretical. If the 0.7 gr of recovered indole acetic acid is taken into consideration, the yield is 89% of the theoretical. The product was purified by vacuum distillation and crystallisation from benzene-petroleum ether to give beautiful glinstering plates.

1 Marvel, C.S. and Tannenbaum, A.L., J. Am. Chem. Soc. 44 (1922) 2646
(Hive Bee)
04-17-03 00:40
No 427399

Hi Vitus!laugh

Here are the cited references from the above article:

72  . H. Najer, R. Giudicelli, J. Loiseau, and J. Menin, Bull. Soc. Chim. Fr., 1963, 2831. 
231 . J. Koo, S. Avakian, and G. J. Martin, J. Org. Chem., 24, 179 (1959).
244a. T. Hoshino and K. Shimodaira, Justus Liebigs Ann. Chem., 5200, 19 (1935).
244b. T. Hoshino and K. Shimodaira, Bull. Chem. Soc. Japan, 11, 221 (1936).
248 . M. E. Speeter and W. C. Anthony, J. Am. Chem. Soc., 76, 6208 (1954).  Retrieved, see Post 450208 (Rhodium: "The Speeter & Anthony Tryptamine Synthesis", Tryptamine Chemistry)
268 . A. F. Ames, D. E. Ames, C. R. Coyne, T. F. Grey, I. M. Lockhart, and R. S. Ralph, J. Chem. Soc., 1959, 3388.
329 . M. Julia, J. Igolen, and H. Igolen,v  Bull. Soc. Chim. Fr., 1962, 1060.[/i]
403 . E. Shaw and D. W. Woolley, J. Am. Chem. Soc., 75, 1877 (1953).
414 . V. Erspamer, T. Vitali, M. Roseghini, and J. M. Cei, Biochem. Pharmacol., 16, 1149 (1967).
435 . W. M. McIsaacs, G. Farrell, R. G. Taborsky, and A. N. Taylor, Science, 148, 3666 (1965).
656 . W. I. Taylor, Helv. Chim. Acta, 33, 164 (1950).
658 . K. Eiter and O. Svierak, Monatsh. Chem., 83, 1453 (1952).
666 . F. Ehrlich, Chem. Ber., 45, 883 (1912). Retrieved, see post above
667a. W. D. McFarlane, K. D. Thompson, and R. H. Garratt, Am. Soc. Brew. Chem., 1963, 98; Chem. Abstr., 60, 6180 (1964).
667b. W. D. McFarlane and K. D. Thompson, J Inst. Brew., 70, 497 (1964); Chem. Abstr., 62, 9739 (1965).
667c. W. D. McFarlane, P. F. Sword, and G. Blinoff, Eur. Brew. Conv. Proc. Cong., 9, 174 (1963); Chem. Abstr., 61, 10006 (1964).
667d. L. Nykanen, E. Puputti, and H. Suomalainen, J Inst. Brewing, 72, 24 (1966); Chem. Abstr., 64, 13352 (1966).
667e. P. Drews, H. Specht, and E. Schwartz, Monatsh. Brau., 18, 240 (1965); Chem. Abstr., 67, 20591 (1967).
668 . D. L. Rayle and W. K. Purves, Plant Physiol., 42, 520 (1967).
669 . R. Rajagopal, Physiol. Plant, 20, 655 (1967).
670 . W. K. Purves, D. L. Rayle, and K. D. Johnson, Ann. N.Y. Acad. Sci., 144, 169 (1967).
671 . R. Rajagopal, Physiol. Plant, 20, 982 (1967).
672 . G. H. Melchior, Planta, 50, 262 (1957).
673 . S. Kveder, S. Iskric, and D. Keglevic, Biochem. J, 85, 447 (1962).
674 . V. E. Davis, J. L. Cashaw, J. A. Huff, and H. Brown, Proc. Soc. Exp. Biol. Med. 122, 890 (1966).
675a. A. Feldstein and K. K. Wong, Life Sci., 4, 183 (1965).
675b. A. Feldstein and K. K. Wong, Anal. Biochem., 11, 467 (1965).
676a. G. Bartholini, A. Pletscher, and H. Bruderer, Nature, 203, 1281 (1964).
676b. M. Da Prada, G. Bartholini, and A. Pletscher, Experientia, 21, 135 (1965).
677 . R. G. Taborsky, P. Delvigs, and I. H. Page, Science, 153, 1018 (1966).
678 . K. Schulte and H. Mueller, Patent DE1233403; Chem. Abstr., 66, 115,600 (1967).
679 . H. J. Enenkel, H. Mueller, and K. Schulte, Patent US3104241; Chem Abstr., 61, 6993 (1964).
680 . R. W. Jackson, J Biol. Chem., 88, 659 (1930). Retrieved, see post above

681 . G. Tacconi, Farm. (Pavia), Ed. Sci., 20, 891 (1965).
682 . H. R. Snyder and F. J. Pilgrim, J Am. Chem. Soc., 70, 3770 (1948).
683 . M. S. Fish, N. M. Johnson, and E. C. Horning, J Am. Chem. Soc., 78, 3668 (1959).
684 . R. C. Elderfield, B. Fischer, and J. M. Lagowski, J Org. Chem., 22, 1376 (1957).
685 . M. Nakazaki, Bull. Chem. Soc. Japan, 32, 588 (1959).
686 . E. Ochiai, M. Takahashi, Y. Tamai, and H. Kataoka, Chem. Pharm. Bull. (Japan), 11, 137 (1963).
687 . P. Delvigs, W. M. McIsaac, and R. G. Taborsky, J Biol. Chem., 240, 348 (1965).
688 . R. G. Taborsky and P. Delvigs, J Med. Chem., 9, 251 (1966).
689 . M. Julia, H. Igolen, and J. Lenzi, Bull. Soc. Chim. Fr., 1966, 2291.
690 . M. Julia, H. Sliwa, and P. Caubere, Bull. Soc. Chim. Fr., 1966, 3359.
691a. R. C. Elderfield and B. A. Fischer, J. Org. Chem., 23, 332 (1958).
691b. R. C. Elderfield and B. A. Fischer, J Org. Chem., 23, 949 (1958).
692a. T. Nogrady and T. W. Doyle, Can. J Chem., 42, 485 (1964).
692b. Upjohn Co., Patent GB778823 (1957); Chem. Abstr., 52, 1265 (1958).
693 . J. Novak, J. Ratusky, V. Sneberg, and F. Sorm, Chem. Listy, 51, 479 (1957).
694 . B. Oddo and F. Cambieri, Gazz. Chim. Ital., 69, 19 (1939).
695 . H. R. Snyder and F. J. Pilgrim, J Am. Chem. Soc., 70, 1962 (1948).
696 . R. A. Robinson, Patent US2908691; Chem. Abstr., 56, 3455 (1962).
697 . M. Julia, Y. Huang, and J. Igolen, C R. Acad. Sci. (Paris), Ser. C 265, 110 (1967).
698 . H. E. Johnson, Patent US3197479; Chem. Abstr., 63, 13217 (1965).
699 . I. Grandberg, A. N. Kost, and A. P. Terent'ev, Zh. Obshch. Khim., 27, 3342 (1957); Chem. Abstr., 52, 9071 (1958).
700 . H. Yamamoto and M. Nakao, Jap. Patent 68:19,952 (1968); Chem. Abstr., 71, 3269 (1969).
701 . N. N. Suvorov, K. B. Kholodkovskaya, and M. N. Preobrazhenskaya, Khim. Geterotsikl. Soedin. Akad. Nauk. Latv. SSR, 265 (1965); Chem. Abstr., 63, 6949 (1965).
702 . J. Szmuszkovicz, J Org. Chem., 27, 515 (1962).

Well, it seems that we have some work to do at the library!cool
(Chief Bee)
07-27-03 21:21
No 450208
      The Speeter & Anthony Tryptamine Synthesis
(Rated as: excellent)

The Action of Oxalyl Chloride on Indoles: A New Approach to Tryptamines
Merrill E. Speeter & William C. Anthony
J. Am. Chem. Soc., 76, 6208-6210 (1954)

Interest in the physiological actions of tryptamine derivatives has been stimulated considerably by the proposals of Woolley and Shawl and Gaddum2 that serotonin (I) may play a role in central nervous system function. The possibility that the remarkable hallucinogenic effects of lysergic acid diethylamide may be due to its effect as a serotonin antimetabolite has been proposed.1,2 These considerations have been complicated by the observations of Stromberg3 and Evarts4 which indicate that bufotenine (II) is itself a hallucinogenic agent5. Apparently, in South America the native use of bufotenine, from the plant piptadenia peregrina,3,6 has been in the past as widespread as the peyote cult of the North American West.7

To obtain bufotenine and its relatives in quantity for study of their central nervous system effects, a new tryptamine synthesis has been developed which appears to be of wide scope and general application. Giua8,9 has claimed that oxalyl chloride reacts with indole to give 2-indoleglyoxylyl chloride. A reinvestigation of these apparently neglected studies has disclosed that the beautifully crystalline product, which is obtained in practically quantitative yield, is 3-indoleglyoxylyl chloride. Giua based his erroneous structure assignment on the observation that 2-indolecarboxylic acid was isolated from a potassium hydroxide fusion of the supposed 2-indoleglyoxylic acid obtained from the acid chloride. Such evidence has been shown to be of doubtful value as a similar alkali fusion led Asahina and Mayeda10 to incorrect structure proposals for the alkaloids rutaecarpine and evodiamine. As early as 1888 Ciamician et al.,11 observed that skatole gave 2-indolecarboxylic acid (mp 203-204°C) on alkali fusion.

Proof of the position of the glyoxylyl chloride substituent on the indole ring was obtained in an unexpected manner when it was observed in our laboratories that lithium aluminum hydride reduction of the amide obtained from the acid chloride and ammonia yielded tryptamine [3-(2-aminoethyl)-indole], while a similar reduction of the ethyl ester of the glyoxylic acid yielded tryptophol [3-(2-hydroxyethyl)-indole].12 Also, a sample of ethyl 3-indoleglyoxylate which was obtained by the method of Oddo and Albanese13 from indole magnesium iodide and ethyl oxalyl chloride did not depress the melting point (183-185°C) of the ester we obtained from the indoleglyoxylyl chloride.

We have found the reaction of oxalyl chloride with indoles offers an attractive approach to a variety of indoleglyoxylic acid derivatives and tryptamines. The reaction has been found to be quite general in application as nicely crystalline glyoxylyl chloride derivatives have been obtained from 2-methylindole, 2-phenylindole, 5,6-dimethoxyindole, 5-acetoxyindole, 5-benzyloxyindole, 6-acetoxy-7-methoxyindole and 1-benz[g]indole. Ethyl 2-indolecarboxylate was unaffected by oxalyl chloride. The excellent yields of amides obtained from the glyoxylyl chlorides together with the facile conversion of the amides to tryptamines in good yield with lithium aluminum hydride have established this route to derivatives of 3-(2-aminoethyl)-indole to be the most convenient of those thus far studied.14

This method has been extended to the preparation of the blood serum vasoconstrictor agent serotonin (5-hydroxytryptamine).15 5-Benzyloxyindole reacted with oxalyl chloride to give a practically quantitative yield of crude 5-benzyloxy-3-indoleglyoxylyl chloride (mp 146-150°C dec.). The acid chloride with dibenzylamine gave a 91% yield of 5-benzyloxy-3-indole-N,N-dibenzylglyoxylamide melting at 150-151°C. When this amide was reduced with lithium aluminum hydride 5-benzyloxy-3-(2-dibenzylaminoethyl)-indole was isolated in 92% yield as the hydrochloride salt, melting at 232-233°C.

This amine was converted to the free base and catalytically debenzylated. The creatinine sulfate complex obtained from the resulting base was identical with the serotonin complex prepared by an earlier method.16 For the preparation of bufotenine, 5-benzyloxy-3-indoleglyoxylyl chloride was treated with dimethylamine to obtain 5-benzoyloxy-N,N-dimethyl-3-indoleglyoxylamide, mp 178-180.5°C.

With lithium aluminum hydride the glyoxylamide gave 5-benzyloxy-3-(2-dimethylaminoethyl)-indole which was isolated as the hydrochloride salt, mp 154-155°C.

Debenzylation of the free base obtained from the above hydrochloride salt gave bufotenine base, mp. 146-147°C. The picrate of this base has been shown to be identical to the bufotenine picrate obtained from pipladenia peregrina.3


(1) D. W. Woolley and E. Shaw, Brit. Med. J., 122-126 (1954).
(2) J. H. Gaddum, Ciba Foundation Symposium, London (1953).
(3) V. L. Stromberg, J. Am. Chem. Soc., 76, 1707 (1954).
(4) E. V. Evarts, Medicinal Chemistry Symposium, Syracuse, N. Y., June, 1954.
(5) Studies by Dr. Nolen Connor of our Laboratories indicate the hydroxyl group is not essential for activity on the central nervous system as 3-(2-dimethylaminoethyl) indole has grossly the same action in the dog as bufotenine. In contrast, 3-(2-methylaminoethyl)-indole has slight activity while 3-(2-n-propylaminoethyl)-indole produced no apparent symptoms.
(6) W. E. Safford, J. Wash. Acad. Sci., 6, 547 (1916).
(7) K. Berlinger, "Der Meskalinrausch" Springer, Berlin, 1927.
(8) M. Giua, Gazz. Chim. ital., 54, 593 (1924).
(9) M. Gina, AW, Congr. naz. chim. ind. Milan, 268 (1924).
(10) Y. Asahina and S. Mayeda, J. Pharm. Soc. Japan, 416, 871 (1916). See also W. O. Kermack, W. H. Perkin, and R. Robinson, J. Chem. Soc., 119, 1615 (1921).
(11) G. Ciamician and C. Zatti, Ber., 21, 1929 (1888).
(12) A somewhat similar hydrogenolysis has since been reported by E. Lette and L. Marion, Can. J. Chem., 31, 775 (1953). These investigators reported the conversion of 3-indolecarboxaldehyde and 3-indole methyl ketone to skatole and 3-ethylindole respectively. A possible mechanism for this conversion is proposed by these workers.
(13) B. Oddo and A. Albanese, Gazz. chim. ital., 57, 827 (1927).
(14) For a review of tryptamine syntheses see P. L. Julian, E. W. Meyer and H. C. Printy, "Heterocyclic Compounds," Vol. 3, John Wiley and Sons, Inc., New York, N. Y., 1952, Chapter 1, pp. 51-57; see also J. Thesing and F. Schulde, Ber,, 85, 324-327 (1952); J. Harley Mason and A. H. Jackson, J. Chem. Soc., 1165 (1954).
(15) M. M. Rapport, A. A. Green and I. H. Page, J. Biol. Chem., 176, 1243 (1948); M. M. Rapport, J. Biol. Chem., 180, 961 (1949).
(16) M. E. Speeter, R. V. Heinzelman and D. I. Weisblat, J. Am. Chem. Soc., 73, 5514 (1951).
(Hive Bee)
12-13-03 03:00
No 476525
      A General Synthesis of Substituted Indoles...
(Rated as: excellent)

Org. Lett., ASAP Article


Web Release Date: December 12, 2003

A General Synthesis of Substituted Indoles from Cyclic Enol Ethers and Enol Lactones

Kevin R. Campos, Jacqueline C. S. Woo, Sandra Lee, and Richard D. Tillyer

Department of Process Research, Merck & Co., Inc., P.O. Box 2000, Rahway, New Jersey 07065

Received October 29, 2003


A general method was developed for the one-pot synthesis of highly functionalized indoles from simple, commercially available aryl hydrazines and cyclic enol ethers. Enol lactones were also used as substrates, affording substituted indole acetic acid or indole propionic acid derivatives. This procedure affords 2,3-disubstituted indoles as single regioisomers from the appropriately substituted enol ether or enol lactone. This method was highlighted in the efficient synthesis of the antimigraine drug sumitriptan and the antiinflammatory drug indomethacin.

The prevalence of indoles in natural products and biologically active compounds has led to a continued strong interest in the practical synthesis of the indole nucleus.1 Among the diverse and creative approaches that have been discovered,2 the Fischer indole reaction remains the benchmark to which other methods are compared.3 Despite being quite versatile, the Fischer indole reaction with aldehydes often suffers from low yields and involves a two-step process (i.e., hydrazone formation, [3 + 3] rearrangement).4 We herein wish to report a convenient and practical one-pot synthesis of 3-substituted indoles from commercially available cyclic enol ethers and enol lactones and the extension of this procedure to the regioselective synthesis of 2,3-disubstituted indoles (eq 1). This methodology is highlighted in the synthesis of several structurally diverse pharmaceutical agents, including the commercial drugs sumitriptan and indomethacin.


In our pursuit of an efficient synthesis of tryptophol homologs, we were intrigued with the possibility of using dihydropyran as an aldehyde equivalent in the Fischer indole reaction.5 We suspected that suitable conditions could be developed that would not only generate the hydrazone from the aryl hydrazine and dihydropyran in situ but also catalyze the [3 + 3] rearrangement in the same pot.

We chose 4% aqueous sulfuric acid as the solvent because of its documented success in promoting the Fisher indole reaction involving the in situ hydrolysis of an aldehyde protected as its dimethyl acetal.6 When dihydropyran was added to a solution of phenylhydrazine hydrochloride in 4% aqueous sulfuric acid at 100 °C, indole 2a was obtained in 50% isolated yield. The major byproduct of the reaction was triol 1, resulting from further reaction of 2a with dihydropyran (eq 2).


We suspected that 1 was produced due to the high concentration of dihydropyran relative to indole product during the reaction; however, slow addition of dihydropyran did not decrease the level of 1 (49%).7 After considerable study, it was discovered that addition of a cosolvent to the reaction significantly improved the reaction profile, producing less than 5% of byproduct 1.8 Of the solvents investigated, acetonitrile (MeCN) and N,N-dimethylacetamide (DMAc) were optimal, affording indole 2a in 85 and 90% yields, respectively.9

The generality of the process was demonstrated with a wide variety of functionalized hydrazines bearing ortho, meta, and para substituents (Table 1).10 In the case of m-tolyl hydrazine, a 1:1 mixture of regioisomeric indoles (2c:2d) was obtained. Aryl hydrazines bearing more than one substituent led to the formation of substituted indoles such as 2k in good yield.

The utility of this method was highlighted in the synthesis of Glaxo's antimigraine drug, sumitriptan (Scheme 1). Despite the documented difficulty of Fischer indole reactions with hydrazine 3 due to the instability of the product under acidic conditions,11 the one-pot reaction could be accomplished to cleanly afford the desired hydroxyindole 4. Activation of the hydroxyl group as the mesylate followed by displacement in the presence of excess dimethylamine according to previously disclosed methodology11b afforded sumitriptan in three steps and 45% overall yield (unoptimized) from dihydropyran.

Scheme 1. Synthesis of Sumitriptan


To expand the scope of the methodology, the reaction of phenylhydrazine with other cyclic enol ethers was investigated (Table 2). For example, reaction of phenylhydrazine with dihydrofuran (5) afforded tryptophol 6 in 72% yield. Interestingly, reaction of 1-methyldihydrofuran (7) afforded the 2,3-disubstituted indole 8 in 83% isolated yield as a single regioisomer.12

Enol lactones also readily participate in this reaction. For example, reaction of enol lactone 11 with phenylhydrazine produced 2-methyl indole propionic acid 12 in 75% yield as a single regioisomer (Table 2, entry 4).13 In contrast, when the procedure was attempted on angelicalactone (13), the cyclic acyl hydrazone 14 was the only observed product.14 This side reaction could be circumvented by installation of an N-benzyl substituent on the hydrazine. Subjection of N-benzyl phenylhydrazine to the same conditions cleanly afforded N-benzyl-2-methylindole acetic acid (16) in 70% yield.

This efficient approach to N-protected indole acetic acids prompted us to apply the method to the synthesis of Merck's antiinflammatory drug, indomethacin.15 Coupling of N-acyl hydrazine 1716 with angelicalactone under standard conditions delivered indomethacin (18) along with a significant amount of deacylated product. We discovered that reduction of the amount of water in the reaction suppressed the deacylation reaction. When the reaction was run with a minimal amount of water, using 1 equiv of sulfuric acid, indomethacin was produced in 65% yield (Scheme 2). This procedure represents a one-step approach to the regioselective synthesis of indomethacin from readily available starting materials.

Scheme 2. Synthesis of Indomethacin


In conclusion, a general, one-pot method for the synthesis of highly functionalized indoles from commercially available cyclic enol ethers and enol lactones has been demonstrated. The procedure is general with respect to both the aryl hydrazine and the enol ether that are used. The method was especially useful for the regioselective synthesis of 2,3-disubstituted indoles. Cyclic enol lactones could be used in this coupling to afford substituted indole propionic acids and indole acetic acid derivatives in an efficient manner. The utility of this method was highlighted in the efficient synthesis of two commercial drugs: sumitriptan and indomethacin. We are currently investigating the application of this methodology to the preparation of highly functionalized indoles. The results of our findings will be reported in due course.


We would like to thank Dr. Jeff Kuethe and Dr. Cheng-yi Chen (Merck & Co.) for valuable comments and discussions.

Detailed experimental procedures and compound characterization data. This material is available free of charge via the Internet at

1. (a) Ihara, M.; Fukumoto, K. Nat. Prod. Rep. 1995, 277. (b) Saxton, J. E. Nat. Prod. Rep. 1994, 493. (c) Saxton, J. E. Indoles; Wiley-Interscience: New York, 1983.
2. For a review of recent developments in the synthesis of indoles, see: Gribble, G. W. J. Chem. Soc., Perkin Trans. 1. 2000, 1045-1075 and references therein.
3. (a) Gribble, G. W. Contemp. Org. Synth. 1994, 1, 1. (b) Hughes, D. L. Org. Prep. Proc. Int. 1993, 25, 607-632. (c) Robinson, B. The Fischer Indole Synthesis; Wiley-Interscience: New York, 1982.
4. (a) Zepeda, L. G.; Morales-Rios, M. S.; Joseph,-Nathan, P. Synth. Commun. 1992, 22, 3243-3256. (b) Shono, T.; Matsumura, Y.; Tsubata, K. J. Org. Chem. 1984, 49, 3711-3716. (c) Fischer, G. W. J. Heterocycl. Chem. 1995, 32, 1557-1561. (d) Pete, B.; Bitter, I.; Szantay, C. J.; Schon, I.; Toke, L. Heterocycles 1998, 48, 1139-1149.
5. This method has been attempted, resulting in low yields as a two-step process. (a) White, J. D.; Yager, K. M.; Yakura, T. J. Am. Chem. Soc. 1994, 116, 1831-1838. (b) McKittrick, B.; Failli, A.; Steffan, R. J.; Soll, R. M.; Hughes, R.; Schmid, J.; Asselin, A. A.; Shaw, C. C.; Noureldin, R.; Gavin, G. J. Heterocycl. Chem. 1990, 27, 2151-2163.
6. (a) Chen, C.-Y.; Senanyake, C. H.; Bill, T. J.; Larsen, R. D.; Verhoeven, T. R.; Reider, P. J. J. Org. Chem. 1994, 59, 3738-3741. (b) Klaver, W. H.; Hiemstra, H.; Speckamp, W. N. J. Am. Chem. Soc. 1989, 111, 2588-2595.
7. Excess hydrazine (2 equiv) slightly reduced the amount of 1 (40%).
8. Importance of the cosolvent is due to the homogenization of the reaction mixture. In purely aqueous systems, the product and dihydrofuran are insoluble, creating a highly concentrated "organic layer" that leads to increased formation of 1.
9. Performing the reaction at 100 °C was optimal. Lower temperatures gave significantly lower yields of 2a (50 °C, 33% yield; 25 °C, 18% yield). However, in the case of more electron-rich hydrazines such as p-methoxyphenylhydrazine, lower temperatures (55 °C) were needed to prevent the formation of the methoxy-substituted analogue of 1.
10. Typical Procedure. To a solution of phenylhydrazine-HCl (1 g, 6.92 mmol) in 4% H2SO4 (aq) (10 mL) and DMAc (10 mL) at 100 °C was added dihydrofuran (630 uL, 6.92 mmol) dropwise over 2 min. The reaction was aged for 2 h and then cooled to room temperature, extracted with isopropyl acetate, and washed with water three times. The crude material was purified by flash chromatography.
11. Highest yield obtained in a Fischer indole with 3 was 63%. (a) Albinson, F. D.; MacKinnon, J. W. M.; Crookes, D. L. U.S. Patent 5103020, 1992. (b) Brodfuehrer, P. R.; Chen, B.-C.; Sattelberg, T. R.; Smith, P. R.; Reddy, J. P.; Stark, D. R.; Quinlan, S. L.; Reid, J. G.; Thottathil, J. K.; Wang, S. J. Org. Chem. 1997, 62, 9192-9202.[Full text - ACS] ( Much lower yields (20-30%) have been reported in most other cases. (c) Dowles, M. D.; Coates, I. H. U.S. Patent 4816470, 1989. (d) Oxford, A. W. U.S. Patent 5037845.
12. Reported difficulty of achieving regioselective Fischer indole cyclizations on unsymmetrical ketones makes this result particularly noteworthy. Zhao, D.; Hughes, D. L.; Bender, D. R.; DeMarco, A. M.; Reider, P. J. J. Org. Chem. 1991, 56, 3001 and references therein.
13. Structures containing this nucleus have been reported to be human neurokinin-1 receptor antagonists and serve as potential therapeutic agents for emesis, anxiety, and depression. Copper, L. C.; Chicchi, G. G.; Dinnell, K.; Elliott, J. M.; Hollingworth, G. J.; Kurtz, M. M.; Locker, K. L.; Morrison, D.; Shaw, D. E.; Tsao, K.-L.; Watt, A. P.; Williams, A. R.; Swain, C. J. Bioorg. Med. Chem Lett. 2001, 1233-1236. Dinnell, K.; Chicchi, G. G.; Dhar, M. J.; Elliott, J. M.; Hollingworth, G. J.; Kurtz, M. M.; Ridgill, M. P.; Rycroft, W.; Tsao, K.-L.; Williams, A. R.; Swain, C. J. Bioorg. Med. Chem. Lett. 2001, 1237-1240.
14. This is a commonly observed intermediate when the N-acylhydrazone forms a six-membered heterocycle. Gouault, N.; Cupif, J. F.; Picard, S.; Lecat, A.; David, M. J. Pharm. Pharmacol. 2001, 53, 981-985.Medline (PMID=11480550)
15. Shen, T. Y.; et al. J. Am. Chem. Soc. 1963, 85, 8-489. Shen, T. Y. U.S. Patent 3161654.
16. This hydrazine could be made in one step according to literature precedent in 90% yield from commercially available starting materials. Karady, S.; Ly, M. G.; Pines, S. H.; Chemerda, J. M.; Sletzinger, M. Synthesis 1973, 50-51.

Table 1. Synthesis of 3-Substituted Indoles from Dihydropyran


a All reactions were run in 4% H2SO4/DMAc (20 mL/g substrate) at 100 °C unless otherwise noted. All reported yields are after isolation by chromatography.
b Reaction was run in 4% H2SO4/MeCN (20 mL/g) at reflux.
c Reaction was run at 55 °C.

Table 2. Fischer Indole Reaction of Phenylhydrazine with Cyclic Enol Ethers and Enol Lactonesa


a All reactions were run in 4% H2SO4/DMAc (20 mL/g substrate) at 100 °C. All reported yields are after isolation by chromatography.
b N-benzyl phenylhydrazine was used in this coupling instead of phenylhydrazine.
c Reaction was run in 4% H2SO4/MeCN (20 mL/g substrate) at reflux.

The candle that burns twice as bright burns half as long
(Chief Bee)
12-27-03 15:19
No 479288
      Synthesis of (Homo)Tryptophol     

Synthesis of (Homo)Tryptophol
Grandberg, I. I.; Afonina, N. I.
Russian Patent SU  239341 (../rhodium/pdf /su239341.pdf) (Retrieved by PolytheneSam)

Tryptophol or homotryptophol are prepd. by treating an arylhydrazine salt with dihydrofuran or dihydropyran (at an elevated temp.) in an aprotic solvent.

Please translate this, russian comrades!

The Hive - Clandestine Chemists Without Borders
(HyperLab Bee)
12-29-03 03:49
No 479561
      OK, here it is
(Rated as: excellent)

To simplify the process, there was approved a method of  tryptophol and homotryptophol synthesis by reaction of arylhidrazine salt with dihydrofuran or dihydropyran by heat on water bath on aprotic solvents.

Example. N-Benzylhomotryptophol.
There was dissolved a 11.7 (0.05 mol) of dry, freshly recrystallized non-symmetric benzylphenylhidrazine hydrochloride in 50 ml of absolute [i.e. anhydrous] dimethylformamide with heat of water bath. After that the solution was cooled to room temperature, there was added a 4.7 g (0.055 mol) of dihydropyrane by one portion. The reaction mixture was slowly refluxed on water bath at 1 hour (before bath boiling) and 1 hour more (after bath boiling). After cooling, the precipitated NH4Cl was filtered off and washed out by benzene. The filtrate was evaporated on water bath to practically dryness. The rest was mixed with 20 ml of water and extracted with hot benzene (3 portions x 30 ml). The extract was evaporated and the rest was distilled in vacuum.
There was 5.6 g (42.2%) of N-Benzylhomotryptophol obtained as an oil with boiling temp. 215-222C (3 mm Hg rt) and melting point 71-72C (from aq. methanol). [some physchem data skipped]

Homotryptophol. It was obtained analogically from previous example from 7.1 g (0.11 mol) of dihydrofuran and 15.9 g (0.1 mol) of non-symmetric benzylphenylhidrazine hydrochloride as an oil with boiling temp. 189-191C (3 mm Hg rt). The yield is 4.5 g (25.7%).
[some physchem props skipped]

P.S. Remarks in - are mine. Sorry for non-fluent english.

With best regards,
Dennis Prochko aka Wolf
(Hive Bee)
01-09-04 03:33
No 481323
      See us 6133453
(Rated as: good read)

Patent US6133453

N'être que de la drogue