Sciencemadness Discussion Board - Indole Synthesis

Indole Synthesis

Waffles SS - 19-12-2009 at 01:57

Fischer indole synthesis:

It seems this is not very difficult.
Anybody has experience/suggestion/better or easier method?

.Fischer, E.; Jourdan, F. Ber. 1883, 16, 2241.
.Fischer, E.; Hess, O. Ber. 1884, 17, 559.
.Van Orden, R. B.; Lindwell, H. G. Chem. Rev. 1942, 30, 69-96.
.Robinson, B. Chem. Rev. 1963, 63, 373-401.
. Robinson, B. Chem. Rev. 1969, 69, 227-250
Source:wikipedia

sonogashira - 19-12-2009 at 02:37

I haven't, but you can look here http://www.orgsyn.org/orgsyn/prep.asp?prep=cv3p0479 in 'discussion' section for alternatives. There is also book called - Indoles best synthetic methods - which you may find interesting. Best luck!

[Edited on 19-12-2009 by sonogashira]

Waffles SS - 19-12-2009 at 03:29

Quote:

passing a mixture of acetylene and aniline through an iron tube at 700.

Majima, Unno, and Ono, Ber., 55, 3854 (1922).

I heve ketene Equipment therefore i think is usefull for this method too.
Anybody has idea or instruction for this method?

[Edited on 19-12-2009 by Waffen SS]

Nicodem - 19-12-2009 at 05:55

Indole itself can not be prepared from phenylhydrazine and acetaldehyde using the most common conditions for the Fischer indole synthesis. The reaction is possible, but requires quite some modified conditions. I already posted about this (references included) in some old thread about the same subject, so UTFSE to find it. However, Fischer indole synthesis can be used to prepare indole indirectly by decarboxylating 2-indolecarboxylic acid prepared from phenylhydrazine and pyruvic acid.

Waffles SS - 19-12-2009 at 06:14

Quote: Originally posted by Nicodem

However, Fischer indole synthesis can be used to prepare indole indirectly by decarboxylating 2-indolecarboxylic acid prepared from phenylhydrazine and pyruvic acid.

Thanks @Nicodem but I need reaction instruction?amount?temp?...?
You have it?

[Edited on 19-12-2009 by Waffen SS]

sonogashira - 19-12-2009 at 07:14

Here is an indole chemistry review. See what is best method to you and then ask for the references for the experimental

Attachment: cr60095a004.pdf (301kB)
This file has been downloaded 6867 times

entropy51 - 19-12-2009 at 07:30

Quote: Originally posted by Nicodem

There is no method to prepare indole itself by using the Fischer cyclisation.
Utmost it is possible to prepare indole-2-caboxylic acid with the Fischer cyclisation of pyruvic acid phenylhydrazone. Indole-2-caboxylic acid can then be decarboxylated to indole.

If you follow that quote back to the thread it came from (click on the green ->

, Nicodem gives some advice about how to find the type of information you seek.

Nicodem - 19-12-2009 at 07:37

Quote: Originally posted by Waffen SS

Thanks @Nicodem but I need reaction instruction?amount?temp?...?
You have it?

Sonogashira already gave you the link to the Org. Synth. entry where you could have looked up for these references:

"Indole-2-carboxylic acid has also been prepared by the Fischer indole synthesis from pyruvic acid phenylhydrazone catalyzed by zinc chloride" : E. Fischer, Ann., 236, 141 (1886); Ber., 19, 1563 (1886).

"...followed by reduction to indole-2-carboxylic acid and decarboxylation of the latter" : Reissert, Ber., 30, 1045 (1897).

Both journals are available online, so you do not even have to visit a library. There surely are other references for this process, but I leave the literature search to others.

Waffles SS - 19-12-2009 at 08:48

phenylhydrazone?
Unfortunately i have access just to phenylhydrazine but i dont have information on phenylhydrazone synthesis.

Nicodem - 19-12-2009 at 11:48

Huh?
Am I mistaken or you never bothered to read about the mechanism of the Fischer indole synthesis even though you posted the scheme of it in the first post above?
I suggest you to check that scheme again, because it nicely says "phenylhydrazone" under the first reaction intermediate.

entropy51 - 19-12-2009 at 13:26

Waffen, I told you that making ketene without a fume hood wasn't good for you!

Waffles SS - 19-12-2009 at 13:37

Ohhhh.
Excuse me i mistaked.
Iam interesting on Reissert indole synthesis because i think is cheaper and easier.
But i dont know instruction and dont have access to online journal(all of online journals that i know arent free).

Reissert, A. Ber. 1897, 30, 1030.

Nicodem - 19-12-2009 at 15:19

Quote: Originally posted by Waffen SS

Ohhhh.
But i dont know instruction and dont have access to online journal(all of online journals that i know arent free).

Reissert, A. Ber. 1897, 30, 1030.

But Berichte is free: http://gallica.bnf.fr/ark:/12148/bpt6k907462.pleinepage.f103...

Using the search engines to obtain information is always a good idea.

Peroxid - 19-12-2009 at 15:24

This is a modified method (the first step is same), but maybe it will be useful!

http://www.orgsyn.org/orgsyn/prep.asp?prep=cv5p0567

[Edited on 19-12-2009 by Peroxid]

Stramonium - 19-12-2009 at 17:23

Out of interest, if one was to heat a homogenous mixture of NaOMe (commercial) and N-formyl-o-toluidine to a high temperature as per http://www.orgsyn.org/orgsyn/prep.asp?prep=cv3p0479 , would the indole be expected to distill off in a reasonable (but lower than that using K-t-BuO) yield? Any need for an initial solvent, or would dry distillation theoretically suffice?

"The cyclization of N-formyl-o-toluidine with sodium in methanol has been described and is recommended as a safer and less expensive method than that involving the use of potassium metal." Galat and Friedman, J. Am. Chem. Soc., 70, 1280 (1948).

Waffles SS - 19-12-2009 at 23:56

@Nicodem,thanks i know Reissert was from deutschland but i dont know germany.

[Edited on 20-12-2009 by Waffen SS]

Nicodem - 20-12-2009 at 02:23

Quote: Originally posted by Waffen SS

@Nicodem,thanks i know Reissert was from deutschland but i dont know germany.

Then why the hell do you use such an irritating german username? Just to annoy us or what? And why did you ask for the information if you did not want it in the first place? And what does it matter if it is in german? Have you never heard of dictionaries and translation machines?

For the internet challenged: http://translate.google.com/

This is the last time I help you. Now I give up.

JohnWW - 21-12-2009 at 16:42

After the War/Whore, members (or at least officers) of the Waffen SS (who were a large elite para-military secret police force, responsible for rounding up and deporting Jews and other dissidents in Nazi-occupied areas to death camps, mostly on the eastern front) were prosecuted in war crimes courts for belonging to a criminal organization. (SS = Schützstaffel). See: http://en.wikipedia.org/wiki/Waffen-SS , http://www.waffen-ss.com , http://www.jewishvirtuallibrary.org/jsource/holocaust/waffen... , http://en.wikipedia.org/wiki/Police_forces_of_Nazi_Germany , http://en.wikipedia.org/wiki/Category:Nazi_SS , http://en.wikipedia.org/wiki/Schutzstaffel , http://en.wikipedia.org/wiki/Gestapo .

I hope you were not among them. You would have to be at least 80 now, to have been; Pope Rat was conscripted into the SS in early 1945 at age 17, one of its youngest members.

BTW When you made your indole, how did you deal with, or suppress, its intense fecal smell? Did you wear a gas mask? Did the neighbors complain? Ironically, in very small amounts, the stuff is used in perfumes.

[Edited on 22-12-09 by JohnWW]

entropy51 - 21-12-2009 at 17:06

Well, John, for once I have to agree with you (I always agree with Nicodem, I'm no dummy), this does seem to be a fairly obnoxious user name. Waffen SS, why don't you re-register with a user name that evokes less memory of crimes against humanity. If not for moral reasons, then because Nicodem is not a source of information to disregard lightly.

John, he hasn't made any indole. He seems to be unlikely to make indole or anything else. Probably not a bad thing.

[Edited on 22-12-2009 by entropy51]

[Edited on 22-12-2009 by entropy51]

Waffles SS - 21-12-2009 at 23:47

My believe is my believe and this is chemistry forum nothingelse,sure i have acceptable reason for my choice and my believe.
back to chemistry
I wanna use indole(iaa,iba) as hormone in some trees(for fast growing,..)

[Edited on 22-12-2009 by Waffen SS]

not_important - 22-12-2009 at 00:38

Have you read the literature on using IAA on woody plants and trees? From what I recall, it really is only effective for the first few months from sprouting, later on it just encourages root growth.

If you are planning the classic synthysis of IAA from indole and glycolic acid, you must have a stirred autoclave for running the reaction at 250 C / 40 atmospheres pressure.

JohnWW - 22-12-2009 at 07:24

Indole as a growth hormone for plants? Actually, it is indole-3-acetic acid, or 2-(1H-indol-3-yl)acetic acid, that is used for this purpose, see http://en.wikipedia.org/wiki/Indole-3-acetic_acid and http://www.super-grow.biz/IAA.jsp among others. It is probably the most important plant auxin, occurring naturally in the apical cells of growing plants. It can be synthesized by the reaction of indole with glycolic acid in the presence of base at 250°C.

[Edited on 22-12-09 by JohnWW]

File_Synthesis_of_indole-3-acetic_acid.png - 22kB

File_Synthesis_of_indole-3-acetic_acid.png - 22kB

not_important - 22-12-2009 at 08:02

Yes, the collection of spineless bullies did say "indole(iaa,iba)" where IAA is a common abbreviation of indole acetic acid, and IBA for indole butyric acid.

The Fischer synthesis can be used to directly produce IIA and IBA or simple derivatives of them, without going through indole in an intermediate step.

Waffles SS - 22-12-2009 at 08:42

I have problem with Fischer indole synthesis For making IAA.
@Nicodem said this reaction need special condition and he suggest Phenylhydrazone+Pyruvic acid but i need more detail about it.
Anyone can send refrence or instruction about that?

entropy51 - 22-12-2009 at 08:44

Quote: Originally posted by Waffen SS

My believe is my believe and this is chemistry forum nothingelse,sure i have acceptable reason for my choice and my believe.

In addition to a chemistry forum, it is a community. Some members of that community may have very personal reasons, such as the murder of relatives by the Waffen SS, to find your "believes" and reasons not acceptable. But suit yourself.

Waffles SS - 22-12-2009 at 09:53

My believe isnot murder of relatives and killing,..or anotherthing,please finish it.
I just love chemistry nothing else.

ScienceSquirrel - 22-12-2009 at 10:42

Really you would be better off just buying it as it is readily available.
Otherwise the way to go is via some of the routes in the discussion section in the preparation below, assuming that you don't have an autoclave handy

http://www.orgsyn.org/orgsyn/orgsyn/prepContent.asp?prep=CV5...

[Edited on 22-12-2009 by ScienceSquirrel]

Polverone - 22-12-2009 at 10:52

Quote: Originally posted by Waffles SS

My believe isnot murder of relatives and killing,..or anotherthing,please finish it.
I just love chemistry nothing else.

I have done you a favor by renaming your account so that any future technical questions of yours can be discussed without distraction.

Satan - 22-12-2009 at 12:32

Quote: Originally posted by not_important

The Fischer synthesis can be used to directly produce IIA and IBA or simple derivatives of them, without going through indole in an intermediate step.

For what derivatives of indole this reaction will also work? Or in other words, wich functional groups would not interfere with normal progres of Fischer synthesis?

[Edited on 22-12-2009 by Satan]

sonogashira - 22-12-2009 at 12:37

It is acid-catalysed reaction, so anything resistant to decoposition by acid (amines, carboxylic acids etc.) is ok I think.

[And maybe, if 'WaffenSS' is changed, 'Satan' is as big a enemy?! Or the only enemy, to some! Hehe!]

[Edited on 22-12-2009 by sonogashira]

ChrisWhewell - 22-12-2009 at 19:35

What do you intend to do with indole ?

hector2000 - 24-12-2009 at 01:14

Quote: Originally posted by Waffles SS

I have problem with Fischer indole synthesis For making IAA.
@Nicodem said this reaction need special condition and he suggest Phenylhydrazone+Pyruvic acid but i need more detail about it.
Anyone can send refrence or instruction about that?

here you are
us2,701,250
process of producing indole3-acetic acid by fischer method

Attachment: US2701250.pdf (237kB)
This file has been downloaded 1010 times

Satan - 24-12-2009 at 11:04

Another document about IAA:

Attachment: Synthesis.Indoleacetic.Acids.Glutamine.pdf (279kB)
This file has been downloaded 1333 times

JohnWW - 24-12-2009 at 11:52

That reminds, me, "Satan": how do Satanists celebrate Christmas? With horns, hooves, a pointed tail, the wings of a bat, goatee beard, red scaly skin, smelling of sulfur (or of selenium or tellurium or polonium, or of indole, if you like), and going around dressed in red tights and brandishing a pitchfork, it must be rather difficult.

Another indole derivative is the purple dye "Tyrian purple", used to dye the robes of Roman Emperors and patricians, originally obtained from two species of whelk, originally called Murex brandaris and Murex trunculus, which are the older names for Haustellum brandaris and Hexaplex trunculus, found in the Mediterranean, in what was a very smelly and costly operation; see http://en.wikipedia.org/wiki/Tyrian_purple . Fortunately the stuff can now be made synthetically. It is 6, 6'-dibromoindigo, a double-bonded dimer of indole via the 5-membered rings, on which there are also keto groups, and there are Br atoms on the aromatic rings.

There is also the important dye indigo, also a substituted dimer via the 5-membered rings of indole, see http://en.wikipedia.org/wiki/Indigo_dye . It was originally obtained from the indigo plant, and is now produced synthetically in large amounts, although not via indole itself.

[Edited on 25-12-09 by JohnWW]

Vogelzang - 24-12-2009 at 12:04

US 3790596 METHOD OF PRODUCING INDOLE AND SUBSTITUTION PRODUCTS OF THE SAME
acetaldehyde phenylhydrazone -> indole

US 3847937 PROCESS FOR THE PREPARATION OF INDOLES
diphenylaminoethane (from aniline and acetaldehyde) -> indole

Also found during the search:
US 2159167 Alcoholic beverage of reduced inebriating capacity

pyruvic acid:
http://www.sciencemadness.org/talk/viewthread.php?tid=8481

[Edited on 24-12-2009 by Vogelzang]

[Edited on 24-12-2009 by Vogelzang]

Vogelzang - 24-12-2009 at 12:09

US 1891057 Production of indole and derivatives thereof

US 2086805 Purification of the isatins

US 2307244 Production of indoles
Page 1 column 1 lines 10+:
It has been proposed to produce indole from indigo by a preliminary reduction with tin and hydrochloric acid followed by destructive reduction with zinc dust at distillation
temperatures. It has also been proposed to produce indole by the distillation of indigo with the aluminum powder at red heat.

US 2365966 Production of indole -> in German Patent No. 260,327 it, is
disclosed that indole may be formed by heating an aqueous solution of indoxyl
and an alkali metal hydroxide in an autoclave to a temperature above 200' C.

US 1657869 Process for producing indigo white

US 1721319 Zn+2NaHSO3=2H+ZnSO3+Na2SO3 ; can be used to reduce indigo to indigo white

US 2130878 Leucoindigo

US 2159930 Preparation of leuco-indigo

US 1588960 Indigo dyestuff
shows structures of indole, indoxyl, isatin, etc.

US 2017120 Production of discharge effects
Page 1 column 2 lines12+:
The zinc compounds of leuco vat dyestuffs have been found particularly convenient for
application in accordance with the present invention, but other insoluble metal compounds may be utilized if desired, for example compounds with cadmium, aluminium, tin, lead or iron. These insoluble metal compounds of leuco vat dyestuffs are conveniently prepared by interaction between the alkali metal salts of the leuco compounds and appropriate metal salts, preferably such as are water-soluble. For instance, the dyestuff in question may be vatted with sodium hyrosulphite or other
reducing agent and just sufficient caustic alkali to yield a solution of the
leuco compound. The solution thus obtained, if desired after filtration,
may be treated with an aqueous solution of the appropriate metal salt, for
example a concentrated solution of zinc chloride, whereby the desired metal
compound of the leuco vat dyestuff may be precipitated.

US 3118724 Processes for reduction of organic substances with alkali-metal borohydrides in the presence of catalysts

US 5350425 Method of reducing vat dyes and the process of dyeing fabrics therein
column 1 lines 49+
Typically, sodium dithionite has been employed to reduce the dyes to
their leuco form, as is shown U.S. Pat. No. 3,798,172. Sodium dithionite
decomposes rapidly in the presence or absence of air; therefore, large, excess
quantities of this compound are used to reduce all of the dye and to maintain
the dye in is soluble leuco form. Regrettably, the use of sodium dithionite
raises ecological concerns.
column 1 lines 64+
Another reducing agent that has received some attention is
thiourea dioxide in an alkaline solution. However, thiourea dioxide is a
strong reducing agent, and therefore tends to over reduce the vat dye. When
reducing indigo overreduction is readily apparent by the smell of fecal
material which is present when indole (the overreduction product) is in the
reaction.
indigo -> leucoindigo using Al, NaOH & H2O column 7, several examples columns 8 and 9

US 2872482 Process of making thiourea dioxide
Column 1
Thiourea dioxide has heretofore been prepared by the oxidation of thiourea by the use of hydrogen peroxide.

US 2150921 Manufacture of imino-amino-methane-sulphinic acid
oxidation of thiourea by the use of hydrogen peroxide

US 2164930 Process for reducing vat dyestuffs
use of thiourea dioxide for reducing vat dyes

unome - 24-12-2009 at 13:45

Attached find a review of the Fischer Indole synthesis.

Waffles SS - 24-12-2009 at 14:24

Thanks @VogelZang and Hector,
@JohnWW now i am Waffles SS,this remind you another thing again?

Vogelzang - 25-12-2009 at 06:46

Ye Ol' zinc dust distillation to remove oxygen atoms.

Indole chemistry began to develop with the study of the dye indigo. Indigo can be converted to isatin and then to oxindole. Then, in 1866, Adolf von Baeyer reduced oxindole to indole using zinc dust.[2] In 1869, he proposed a formula for indole (left).[3]

2. Baeyer, A. (1866). "Ueber die Reduction aromatischer Verbindungen mittelst Zinkstaub". Ann. 140: 295. doi:10.1002/jlac.18661400306.

3. Baeyer, A.; Emmerling, A. (1869). "Synthese des Indols". Chemische Berichte 2: 679. doi:10.1002/cber.186900201268.

http://en.wikipedia.org/wiki/Indole

[Edited on 25-12-2009 by Vogelzang]

Vogelzang - 25-12-2009 at 06:57

This discusses the production of indole from pyrrole (page 629).

http://books.google.com/books?id=MAA5AAAAIAAJ&pg=RA1-PA6...

[Edited on 25-12-2009 by Vogelzang]

Satan - 25-12-2009 at 14:40

How would react hydrazone, made from condensation of 4-methoxyphenylhydrazine and acetaldehyde? There are two possible reaction products, 5-methoxyindole and 6-methoxyindole. My true question is: how to predict how substitiued phenylhydrazones would cyclicyze?

From 5-methoxyindole, melatonin can be made, it would be interesting synthesis of human hormone.

sonogashira - 26-12-2009 at 02:47

Quote: Originally posted by Satan

From 5-methoxyindole, melatonin can be made, it would be interesting synthesis of human hormone.

If it is your interest there is this thread by a person now-departed from this site, God bless him

Lot of good alternative methods and (maybe!) even the one you have an interest in...
http://www.sciencemadness.org/talk/viewthread.php?tid=10120

[Edited on 26-12-2009 by sonogashira]

Vogelzang - 27-12-2009 at 13:22

US patents which disclose processes for producing indoles from phenylhydrazones: 4965369, 5229413, 2995566, 1866956, 2057948, 2068800, 3557142.

Vogelzang - 27-12-2009 at 13:54

Another US patent on IAA 2701251.

US patents on anilines + glycols -> indoles: 4436916, 4436917, 4443615, 4456760, 4473698, 4474969, 4476310, 4659841, 4727161, 4732654, 4831158, 4937353, 5175308, 4404063 (with indole separation).

An interesting tryptamine process: US 5037845

unome - 8-1-2010 at 00:20

Damn, I thought my attachment attached, obviously not here tis again...

B. Robinson, The Fischer Indole Synthesis, Chem. Rev., 1963, 63 (4), pp 373–401 (DOI: 10.1021/cr60224a003)

Rattata2 - 14-1-2010 at 18:02

I like this idea:

React benzaldehyde with nitroethane forming a beta-nitrostyrene. Nitrate this with HNO3 - this should nitrate mostly ortho-. Follow by heating with iron turnings to form indole.

unome - 14-1-2010 at 22:57

Why aren't the attachments working?

There should be 4 attached here NOW :mad:

Attachment: VanOrder.Lindwall.Chem.Review.Indole.pdf (306kB)
This file has been downloaded 1661 times

Attachment: Bidylo.Yurovskaya.Synthesis.Tryptamines.Latent.AminoButanal.Review.pdf (835kB)
This file has been downloaded 8624 times

Attachment: indole.synth.review.1994-99.pdf (791kB)
This file has been downloaded 2775 times

Attachment: Improved.Synthesis.DMT.Psilocin.pdf (1.4MB)
This file has been downloaded 1325 times

[Edited on 15-1-2010 by unome]

Rattata2 - 31-1-2010 at 06:14

Whoops I meant nitrom*ethane in the previous post. My bad, makes things easier eh? :p

Anyways, I found this recently which to me looks like an exciting method of indole synthesis: http://www.sciencedirect.com/science?_ob=ArticleURL&_udi...

I can't access the paper myself (anyone who can if you wanna upload it thatd be great) but the abstract says wonders..it's a fischer indole synthesis using pyruvic acid as the ketone, under microwave irradiation (with ZnCl2 as a catalyst.) This would first form indole-2-carboxylic acid as an intermediate which would then be decarboxylated to yield indole. Apparently in a microwave, this whole procedure can be done in a one-pot synthesis

Not sure if the PCl5 is really required for this (it isn't for classical fischer indole synthesis is it?), but I do believe the reaction is supposed to take place in acidic conditions. Anyways hope this turns out useful to someone

IPN - 31-1-2010 at 06:43

Here is the full paper.

Attachment: A new and efficient one-pot synthesis of indoles.pdf (95kB)
This file has been downloaded 2827 times

Waffles SS - 31-1-2010 at 09:19

One funny question:
May we use kitchen microwave oven for microwave irradiation step?

Evilblaze - 31-1-2010 at 09:44

Quote: Originally posted by Waffles SS

One funny question:
May we use kitchen microwave oven for microwave irradiation step?

Not a really good idea, the kichen microwave ovens are not designed for chemistry. It will heat it up too much and the small amount of the irradiated compound will cause some problem. Place a large cup a water next to the chemical and hope the best. If you are lucky, than the microwave oven will survive.

Read this:

http://www.cem.de/images/produkte/mikro_synthese/attsqqrb.pd...

and make a similar thing.

Waffles SS - 31-1-2010 at 11:49

There is microwave irradiation device for buy(for use in chemistry)?

Rattata2 - 31-1-2010 at 12:33

IPN: Thanks for the paper

Like I thought it pretty much says what I figured it would. The PCl5 is used to remove water from the reaction - which I'm not sure if very small amounts of water would necessarily hurt anything seeing as microwaves would likely boil it out anyways..but I'm sure that it would only increase yields.

I'm assuming from various simple experiments that a household microwave would probably suffice to do most reactions..however with something like this wherein you're using hydrazines (and coming out with potentially smelly chemicals :p), I think it would be wise not to use the same one you eat from. If you can't build a microwave specific to the purposes, at least spend the $50 on one for chemical use only. And refrain from heating your burritos in it during your lab breaks :p

And just wanted to note that this reaction would probably work just fine if done via conventional heating as well..only the decarboxylation step may have to be done separately.

I'm also thinking that if one wanted to keep that 2-carboxylic acid group for whatever reason, or wanted to maintain purity during the reaction (say when doing conventional heating, as to not obtain a mixture of indole and the 2-substituent) they could protect it with an ester. This could then de-esterified and decarboxylated at once. Prolly unnecessary for most ppl but some might find that useful.

[Edited on 31-1-2010 by Rattata2]

Rattata2 - 9-2-2010 at 18:28

Another addition to this thread

Not sure where I found this but it could be useful!
--
"Polikier (317) heated the dianilide of tartaric acid with zinc chloride to obtain indole; dianilinosuccinanilide was an intermediate."

edit: Just found this in Journal - Chemical Society, London, Volume 62, Part 1

polkier indole 1.jpg - 136kB

http://books.google.com/books?id=HsIwAAAAYAAJ&pg=PA66&am...

[Edited on 10-2-2010 by Rattata2]

zed - 26-7-2010 at 11:53

I'm going to go back and read all of the references in this thread. But I do have a number on hand.

I have inspected the system to synthesize IAA via glutamic acid. It doesn't produce a high yield, but it might work. And, it does something that many of us find very attractive.....Assuming you can obtain Phenylhydrazine, it uses common materials.

http://www.freepatentsonline.com/2701251.pdf

As for the Fischer synthesis itself, I have utilized it many times.

In the past, I have used it to produced 2-Methyl Indole, 2-Phenyl Indole, Tetrahydrocarbazole, and 2-Methyl-N.N-Diethyl-Tryptamine.

The method is slam-dunk simple, and it works.

The method being proposed for the microwave synthesis of indole from pyruvic acid is so similar to the method that I used to produce 2-methyl indole, that I would try to interchange the two. Without the use of a special microwave oven, which most of us don't have.

From memory, I did the following.....I combined Acetone with Phenylhydrazine, in a large beaker, with a modest amount of absolute alcohol, then I warmed the material on a hot-water bath for an hour or so. Next, I proceeded to raise the temperature enough to boil off the solvent. The alcohol leaves, taking H2O with it. The liquid phenylhydrazone is left behind.

Next, you melt some ZnCl2 in a big beaker, heat it until it become fluid. and with vigorous glass rod stirring, you gradually mix in the Phenylhydrazone.

That's it. You let it cool a bit, dissolve the Zn Chloride, and you have fairly impressive yield of 2-Methyl Indole.

I'll see if I can dig up the exact procedure.
-------------------------------------------------------------------

OK, I cruised the web a little. Reaction conditions....Cyclization with ZnCl at 180 C.............Decarboxylation of 2-carboxylic acid to produce indole............240C
-------------------------------------------------------------------
I'll see what else I can find.
-------------------------------------------------------------------
"Since the time of this early work a number of changes have been introduced into the method, with improvement in the yields. Thus it was found (91) that by the use of an inert solvent such as methylnaphthalene, and by keeping the
temperature below 15O0C, acetone phenylhydrazone gave a 75 per cent yield of 2-methylindole, propionaldehyde phenylhydrazone an 80 per cent yield of skatole, and the phenylhydrazone of pyruvic acid gave a 60 per cent yield of indole-2-carboxylic acid."
------------------------------------------------------------------------------
From Acetaldehyde Phenylhydrazone, sadly it appears the method requires running the phenylhydrazone through a tube-furnace type set-up. http://www.google.com/patents?id=SXM7AAAAEBAJ&printsec=a...

I very much like the one-pot microwave method yielding 88% Indole from phenylhydrazine and pyruvic acid. But, it has a few problems. PCl5 isn't easy to come by, and the synthesis produces less than 3mmoles of product. Fine for an experiment...But, can it be scaled up?

[Edited on 27-7-2010 by zed]

[Edited on 27-7-2010 by zed]

Waffles SS - 22-8-2013 at 22:11

Quote:

The Baeyer–Emmerling indole synthesis is a method for synthesizing indole from a (substituted) ortho-nitrocinnamic acid and iron powder in strongly basic solution. This reaction was discovered by Adolf von Baeyer and A. Emmerling in 1869
http://en.wikipedia.org/wiki/Baeyer-Emmerling_indole_synthes...

This is interesting method and i like to try it.

O-Nitro Benzaldehyde:
-Toluene nitrate and O isomer separate by cooling.
-O,Nitro benzyl chloride prepare by reaction of Sulfuryl chloride with ONT.
-O,Nitro Benzaldehyde prepare by reaction of Hexamine with O,Nitro benzyl chloride.

O-Nitro Cinnamic Acid(Method1):
Cinnamaldehyde can also be nitrated, e.g. in a solution of acetic anhydride in acetic acid, in high-yield to 2-nitrocinnamaldehyde.This compound is then oxidized to 2-nitrocinnamic acid
http://www.orgsyn.org/orgsyn/prep.asp?rxntypeid=181&prep...

O,Nitro Cinnamic acid(method2):
-O,Nitro Cinnamic acid prepare by Perkin reaction(Acetic Anhydrid + O,Nitro Benzaldehyde +KOAC)

Final step is "Baeyer–Emmerling indole synthesis" that i dont have detail of this reaction(i just know Iron and KOH is needed)

Indole:
Somebody has more information or instruction about this route?i didnt find any useful information.

[Edited on 23-8-2013 by Waffles SS]

AndersHoveland - 22-8-2013 at 23:17

Quote: Originally posted by Waffles SS

How readily does the enamine to the imine step proceed?
Is it spontaneous, or does it require refluxing?