catastrophe
(Hive Bee)
05-14-03 13:46
No 433179
      Aralkyl halides to Thiols
(Rated as: excellent)
    

This is the continuation of a discussion found in this thread: Post 432858 (Rhodium: "Sodium Hydrogen Sulfide solution preparation", Chemistry Discourse)

Unfortunately SWIM does not remember the book the reference is from. But fortunately, and more importantly, SWIM photocopied the page that the book stated they got the ref. fromsmile. Here's what they say...

Aralkyl halides react smoothly with thiourea in DMSO to give sulfhydryl derivatives.12a

ArX + S=C(NH2)2 + NaOH ---DMSO, 25C, 99%---> ArSH

12a refers to : H.-L. Pan and T.L. Fletcher, Chem. Ind., 546(1968)

Well, this is quite useful if it turns out to work on aromatic aldehydes, which there is no reason it shouldn't. Syntheses for 4-bromo-2,5-dimethoxybenzaldehyde and 5-bromovanillin can be found on Rhodium's, and the corresponding amines are well documented in PihKaL.

Noller's "Chemistry of Organic Compounds" 265(1951), provides a nice explanation of what happens in this displacement reaction...

Alkyl halides react with thiourea to give S-alkylthioureas (catastrophe: AKA alkyl-isothioureas), which on heating yield mercaptans and dicyanamide.

                                   NH2                           NH2
                                   |                               | 
RX + S=C(NH2)2  --->  RSC=NH2+X- --NaOH--> RSC=NH + NaX + H2O

    NH2
    |
RSC=NH  --heat--> RSH + H2NC=

catastrophe: Two moles of H2NC=N (cyanamide) react to form dicyanamide. Sorry, couldn't/didn't want to draw it.

As you can see, a little ambiguity arises. One procedure dit que heat is required during the alkaline hydrolysis of the isothiourea hydrohalide, while the other states the entire reaction is at r.t.. If somebody can obtain the above reference so that we can see the reaction details, this matter can be hashed out. Perhaps the choice of DMSO as a solvent circumvents the need for heating?

Another useful reference comes from Japanese Patent 63203632, rough translation found at Rhodium's : ../rhodium/chemistry /thiophenol.thiourea.html
Here, the use of glacial acetic acid seems to produce very acceptable yields. But again, there is no mention of heating the reaction to convert the alkyl-isothiourea to the free thiol after the base has been added. Of course a little heating shouldn't cause any trouble though.


SWIM had planned on trying this reaction out on 5-bromovanillin during late August, when he/she had the time. However, since Chimimanie brought it up, SWIM would not at all be jealous if somebody wanted to give it a shot before him/her wink.
As a matter of fact, if you want, SWIM had several ideas of how to seperate the unreacted 5-bromovanillin from the 5-mercaptovanillin (which will be an issue in this rxn). SWIM has made 5-bromovanillin via oxone/NaBr/vanillin in 70% EtOH, and also in much better yield by gassing vanillin in MeOH with Br2(g).

In any case, SWIM will give it a try in ~3 months time, so either wait or try it yourself.

PS. SWIM also has a paper detailing lauryl bromide --> lauryl mercaptan via thiourea refluxing in 95% EtOH with 83% yield. Also remember reading a paper from a belge chemist detailing something similar. Hmmmmm, don't you just love sulphur compounds?
 
 
 
 
    catastrophe
(Hive Bee)
05-14-03 13:51
No 433181
      Sorry     

Yuck, sorry for those really shitty drawings frown. SWIM doesn't have a molecular drawer, so you might want to maximize your browser for it to make some sense. Hope SWIM got all of those amino groups on the carbon correctlycrazy.

Also for the first reference, they didn't state ArX, they had an actual compound. But again, SWIM couldn't draw it so he/she just generalized for you.

Edit: The compound they used in the ref. was diphenylbromomethane. Yes sir, the same compound used in the Modafinil synth posted by Antoncho. Except in this case they hydrolysize the isothiourea hydrobromide to the free thiol.
 
 
 
 
    catastrophe
(Hive Bee)
05-16-03 10:32
No 433580
      Alternatives     

Okay, it was incorrect to "generalize" ArX --> ArSH, as the reference states that it will only work for aralkyl halides, no mention of aryl halides. Also, as Chimimanie pointed out, no reference, including the Japanese Patent at Rhodium's, gives specific examples using aromatic halogens, only pyridines(close!), thiazoles, and alkyl halides.

Here is the translated abstract from the Japanese Patent:

PURPOSE:To obtain the titled compound which is an intermediate for agricultural chemicals, medicine, dye, etc., in good yield, by reacting a halide compound with thiourea in the presence of an aliphatic carboxylic acid or anhydride thereof in the reaction system and treating the reaction product with an alkaline substance.
CONSTITUTION:A halide compound (e.g. 2-chloro-3-trifluoromethyl pyridine, etc.) expressed by the formula R-X (R is alkyl, benzyl, aromatic heterocycls having 5-6 members) is reacted with thiourea in the presence of an aliphatic carboxylic acid (e.g. acetic acid, etc.) or acid anhydride thereof (preferably having 50-200wt.% based on the halide compound) and the reaction product is treated with an alkaline substance to provide the aimed thiol compound (2-mercapto-3-trifluoromethylpyridine, etc.). No offensive odor is caused during reaction treatment, but also reaction yield is greatly improved.




Chimimanie, if worst comes to worst, then the next best route to the 2C-T-X's would be...
First S-monoalkylate 2,5-Dihydroxythiophenol to get the 2,5-Dihydroxyphenyl alkyl sulphide described here by Rhodium Post 360999 (Rhodium: "2,5-Dihydroxythiophenol and alkoxy derivatives", Novel Discourse), then methylate to get the 2,5-Dimethoxy config. Or possibly just start from here Post 207554 (Antoncho: "An easy OTC 2,5-diMeO-phenylmercaptan", Novel Discourse)? Chloromethylate via the procedure that you kindly posted here Post 423119 (Chimimanie: "Synthesis of 2-Chloromethyl-5-alkylthio-DMB", Methods Discourse). From here, do a Sommelet as described in Patent US4321412 to obtain the aldehyde. A little work, but it is definetly do-able. Also, the dioxane from the chloromethylation can be made OTC from acid hydrolysis of ethylene glycol. Do you think paraformaldehyde can be substituted for formalin??

The other alternative, if you even want to call it an alternative, is to perform the procedure on Rhodium's with the free thiolates (the smell will be unbearable), ../rhodium/chemistry /4-alkylthio-25-dmb.html. The thiolates CAN DEFINETLY be made from thiourea, but that smell will just be horrible. Fischer found that the nose can detect one volume of ethyl mercaptan in 50 billion volumes of air!!! If you don't work in a professional/academic lab, then the synth is probably out of the question unless you live miles away from anything.

But, SWIM will not give up on this thiourea reaction on the straight aryl halide until he/she proves it not to work on 5-bromovanillin first. SWIM has to find a way to the 2C-T's, any obscure ideas are always welcome (AHHM, Yellium how about that Grignard with sulphur and 2-bromo-1,4-dimethoxybenzene?)

 
 
 
 
    catastrophe
(Hive Bee)
05-17-03 15:26
No 433783
      Well, as usual nobody is interested in what...     

Well, as usual nobody is interested in what SWIM is interested in (2C-P, 2C-G-X, thiols) so, he/she will just mention/ask one last thing...

Can anybody recommend something that will neutralize the smell of a thiol? Is there a solution SWIM can prepare where if you bubble say ethanethiol into it, the odour/thiol will be neutralized??

SWIM was contemplating a one-pot reaction where you could prepare the ethanethiol in DMSO as in the reference "aralkyl halides react smoothly with thiourea in DMSO to give sulphhydryl derivatives" with ethyl bromide, thiourea, and NaOH. Then, without isolating the ethanethiol, directly add to the solution 4-Br-2,5-dimethoxybenzaldehyde and some K2CO3, assuming cyanamide doesn't cause complications. DMSO can surely be substituted for DMF in ../rhodium/chemistry /4-alkylthio-25-dmb.html, as their both good polar aprotic solvents for nucleophilic substitutions. What do you guys think? (translation: What do you think Rhodium?)
 
 
 
 
    yellium
(I'm Yust a Typo)
05-17-03 15:30
No 433784
      When I had to clean glassware that had been in     

When I had to clean glassware that had been in intimate contact with thiols, I used 1M KOH. Worked like a charm; the idea behind it being that thiols are slightly acidic. Don't know if it works so good that you can bubble thiols through a basic solution and smell nothing.
 
 
 
 
    Chimimanie
(Hive Bee)
05-22-03 18:29
No 434844
      Review     

I started a review on that topic:
Post 434950 (Chimimanie: "On 2C-T-x precursors", Novel Discourse)

Please can the bees post all comment regarding synthesis of 2CT compounds here.

I will update the review when new roads will come, hopefully one with the reaction of thiourea on an aromatic halogen, but I doubt we will ever found it. I will discute this point later.

BTW, I dont think ethanethiol stink THAT bad, it doesn't disturb me that much (way less than pyridine for instance!), but the smell is detectable two houses away. Hopefully you dont need to do it with the ballon open, just put a stopper on the RBF, wrap it in a plastic bag and let it stir. No smells are detectable that way.
 
 
 
 
    catastrophe
(Hive Bee)
05-23-03 11:21
No 434998
      Odourless?     

From the digest...

It involve the reaction of dimethoxybenzene with chlorosulfonic acid, to yield 2,5-dimethoxybenzenesulfonyl chloride, then he reduct that with Zn dust to 2,5-dimethoxythiophenol in 35% yield. The reaction look not hard and is odorless according to Yellium.




The reduction with Zn/HCl gives off much H2S gas, being both poisonous and smelly.

SWIM really likes the idea of the one-pot reaction, preparing the proper thio nucleophile in the DMF (or DMSO), then just adding the 4-Br-2,5-Dimethoxybenzaldehyde. Seems like it could work odourless and very simple. Well, we'll seewink.

BTW. Chimi, do you know if the S-Ethylthiourea hydrobromide is smelly? Or is it just the free thiol?? Nice procedure.

 
 
 
 
    Rhodium
(Chief Bee)
05-23-03 13:19
No 435013
      H2S in reductions of sulfonates to thiophenols?     

Why would the reduction of 2,5-Dimethoxyphenyl-chlorosulfonate with Zn/HCl give off H2S?

Preparation of the chlorosulfonate:

2,5-MeO-Ph-H + 2 ClSO3H 2,5-MeO-Ph-SO2Cl + HCl + H2SO4 (HCl gas is produced)

Reduction of the chlorosulfonate:

2,5-MeO-Ph-SO2Cl + Zn + HCl 2,5-MeO-Ph-SH + H2O + ZnCl2 (The only gas produced would come from Zn + HCl ZnCl2 + H2)
 
In Pihkal #40 (2C-T-2), the good doctor uses H2SO4 instead of HCl as proton source in the reduction, and in that case, one equivalent of HCl is produced as the chlorosulfonate is reduced, and in the presence of heat and strong sulfuric acid this may evaporate, but still no H2S.

Perhaps you are thinking of the synthesis of 2,5-dihydroxythiophenol in Pihkal #39 (2C-T), where sodium 2,5-hydroxyphenylthiosulfate is being reduced with Zn/HCl? In that procedure H2S is indeed formed.

Reduction of Sodium 2,5-Dihydroxyphenylthiosulfate:

2,5-OH-Ph-S-SO3Na + Zn + HCl 2,5-OH-Ph-SH +  ZnCl2 + H2O + H2S + H2
 
 
 
 
    catastrophe
(Hive Bee)
05-24-03 13:49
No 435237
      You're right     

You're right. SWIM was thinking of the reduction of the thiosulphate with the S-alkylation you posted Rhodium. Sorry crazy. Thanks for writing out those reduction steps too. They are useful for SWIM and other bees.

About saponification of the reaction between potassium ethyl xanthate with the diazo compound, SWIM has read it can result in very violent explosions. Anybody have any experience in such reaction?? Chimi, where did you get the 50% yield reference from, that looks very interesting. This is the A:M:N:C route described on the digest.
Edit: Okay thanks Chimi, saw the update of the digest. Looks interesting.

Chimi, you sayed above...

BTW, I dont think ethanethiol stink THAT bad, it doesn't disturb me that much (way less than pyridine for instance!), but the smell is detectable two houses away. Hopefully you dont need to do it with the ballon open, just put a stopper on the RBF, wrap it in a plastic bag and let it stir. No smells are detectable that way. 



Does this mean you tried the SN2 reaction described on Rhodium's?? If yes, could you please describe how it went. Does the carbonate go into solution? This method has recently become the apple of SWIM's eye. Hopefully you can substitute DMSO for DMF.

Patent US2761873 looks to be the most ideal method. Check out Example 7 with the p-Cl-benzaldehyde. And it's all performed in EtOH.

 
 
 
 
    Chimimanie
(Hive Bee)
05-25-03 10:27
No 435446
      I tried it, sort of. I did it but not on ...     

I tried it, sort of.

I did it but not on bromo-dimethoxybenzaldehyde, as I understood later that the compound I had obtained was not the aldehyde. It may have been dimethoxybenzene or bromo-dimethoxybenzene, i dont remember very well, it was a long time ago.

The reaction was done like in the spanish article on rhodium's. It is done in the cold and there is no problem to do it in a closed system.

You are right about the potassium ethyl xanthate, it is dangerous, see ../rhodium/chemistry /3-hydroxythiophenol.html. I didn't like that route anyway, it is low yielding and too much work. The best route (if 2,5 DMB is unavaiable) will bee the copper catalysed swap with alkyl thiol, see the excellent post made by Lego: Post 431985 (Lego: "Bromobenzenes to Butylthiobenzenes", Novel Discourse).

Yes, DMSO could most probably be substituted for DMF.  

As for the pyridine ref (aromatic bromide => thiol using thiourea): I dont think it will work with our compounds, because I never saw a single ref with that reaction on compound with activating group. Always they are nitro aromatic or benzaldehyde. Look also at the reaction from bromo-2,5 dmb,  the authors tell explicitely that they think it work because the ring is deactivated by the aldehyde. Our straight dimethoxy benzene rings could not do that thiourea swap. But its not that bad if the copper exchange with alkylthio work. I hope that copper reaction will work with secondary and tertiary thiols too. (otherwise bye bye 2C-T-4 and Nimitzfrown)

The isothiouronium salt dont smell bad (at least not for modafinil), beside its own slow hydrolyse to the free thiol of course. The thiolate solution smell bad even if it is stongly basic.

If you are very concerned with odors, there is an orgsyn ref where they neutralise it with an oxydising solution, i will search it.
 
 
 
 
    catastrophe
(Hive Bee)
05-27-03 13:54
No 435925
      More good refs...
(Rated as: excellent)
    

Patent US2761873 - By far the most promising route in SWIM's opinion. Mentioned it in the previous post, but it is really nice and very feasible.

Patent US5298630 - Very nice patent on synthesis of mercaptobenzaldehydes. Mentions Patent US2761873 above, and gives good reaction details and drawbacks to various methods. Gives good references.

Patent US6025526 - also good, but a little impractical.

Patent US2410431, Patent US2321468 & Patent US2173827 - these three are all related. SWIM just read the first few lines of the patents and smiled!! Similar to greater potency than cocaine?? Patent US2321468 makes a mention of the potassium ethyl xanthate route at the bottom of the first page. Do you think these compounds can be taken orally??

Patent US4187319 - SWIM just thought it was an interesting patent. Not very useful, but nice reading. They use very long chains (10-20 carbons) of fatty acids to add to mercapto-benzaldehydes.

SWIM is a little concerned in noticing that most people are only interested in the 2C-T-X thiol compounds, but there are many other good thiol compounds in pihkal that SWIM is interested in as well. He/She wants to find a route for all of these compounds, whether it is at the meta position or the para or the ortho.
Somebody, anybody, do you guys think that Patent US2761873 will work for m-halobenzaldehydes??? Patent US6025526 says it will work for both ortho and para positions, do you think it will work for meta too???

BTW Thanks for responding Chimi. smile
 
 
 
 
    Chimimanie
(Hive Bee)
05-27-03 17:41
No 435958
      Our old friend Poix
(Rated as: excellent)
    

No prob catastrophewink.

Our old friend Poix (Hello Poix!smile) posted a part of this article bee4 Post 217440 (poix: "Re: Preparing alkylthio Benzaldehydes  2CT2, 2CT7", Chemistry Discourse), but nobody posted it entirely.

Catastrophe I think you will find it relevant to your projectswink.

Facile synthesis of alkylthiobenzaldehydes John A. Schwartz, Synthetic Communications, 16(5), 565-570 (1986)

Abstract:

Alkoxyl alkylthiobenzaldehydes can be readily prepared from the corresponding bromobenzaldehydes and the sodium salt of primary mercaptans in DMF.

During the course of our research we required various alkoxyl alkylthio substituted benzaldehydes. Examination of the Literature revealed that classical methods[1] might be suitable but cumbersome. Several workers[2] have developed efficient methods for the preparation of 2-alkylthiobenzaldehydes. However, attempted preparation of alkoxyl substituted benzaldehydes using these methods resulted in extensive 0-dealkylation. Thus a method for the synthesis of alkylthio substituted benzaldehydes which would accommodate the presence of alkoxyl substituents was investigated. Reaction of the known alkoxyl substituted 2-bromobenzaldehydes 1a-e with the sodium salt of primary[3] mercaptans in DMF provided good to excellent yields of the alkylthiobenzaldehydes shown in Table II and Table III.

The facile nature of this reaction is due presumably to the activation effect of the aldehyde group.[4] Aldehydes with bromine substituted in the para position react similarly (see Table IV). However, aldehydes with bromine substituted in the meta position to the carbonyl are unreactive under these conditions.

The low yields of the methylenedioxy substituted products 2d and 3d result from cleavage of the ether by the nucleophilic sulfur reagent. In the case of the sterically congested 2-bromo-3,4,5-trimethoxybenzaldehyde (1f), reaction with the sodium salt of methyl mercaptan is very slow and affords a 80% yield of unreacted aldehyde 1f with the remainder being dehalogenated aldehyde. Reaction of 1f with the sodium salt of benzyl mercaptan gave only recovered starting aldehyde.

Although this method is limited to the use of primary mercaptans and sterically unhindered aldehydes, it offers a simple and efficient method for the preparation of oxygenated alkylthiosubstituted benzaldehydes from readily available precursors.


Table I
  R1 R2 R3 Reference
1a H H OMe 5
1b H OMe OMe 6
1c H OMe OBn 7
1d H O- -MeO 8
1e H Me OMe 9
1f OMe OMe OMe 10


Table II
Cmpd R1 R2 R3 Yield mp(C)
2a H H OMe 71% 53-54 (hexane)
2b H OMe OMe 87% 111.5-112 (ethanol) [1]
2c H OMe OBn 92% 88-89 (hexane)
2d H O- -MeO 49% 101.5-102 (ethanol)
2e H Me OMe 86% 61.5-62 (hexane) [2a]


Table III
Cmpd R1 R2 R3 Yield mp(C)
3a H H OMe 79% 190-191.5 (methanol) (2,4 DNP derivative)
3b H OMe OMe 80% 67.5-68 (isopropanol) [1]
3c H OMe OBn 80% 121.5-122 (methanol)
3d H O- -MeO 69% 88-88.5 (isopropanol)
3e H Me OMe 73% 155-155.5 (methanol) (2,4 DNP derivative)


Table IV
Cmpd R Yield mp(C)
4a Br   see ref [10]
4b SMe 89% 94.5-95.5 (isopropanol)
4c SBn 95% 122.5-123 (isopropanol/hexane)



1:











Molecule: 1 ("O=Cc1cc([R3])c([R2])c([R1])c1Br")


2:











Molecule: 2 ("CSc1c([R1])c([R2])c([R3])cc1C=O")


3:











Molecule: 3 ("O=Cc1cc([R3])c([R2])c([R1])c1SCc2ccccc2")


4:











Molecule: 4 ("COc1cc(C=O)c(OC)cc1[R]")



General procedure:

To a stirred suspension of sodium hydride (11 mmol, 0.44g, 60% dispersion in mineral oil) in 25 ml of DMF under nitrogen atmosphere and cooled in an ice-water bath was added 11 mmol (1.31g) of benzyl mercaptan. (In the case of methyl mercaptan, the gas was passed above the DMF solution until the sodium hydride was consumed.) After the sodium hydride was consumed, the appropriate bromobenzaldehyde was added in one portion and the reaction mixture was allowed to warm to room temperature overnight. The reaction mixture was poured into 400 ml of water and the precipitated product was filtered and air dried. (In the case of 3a and 3e, the products were extracted with methylene chloride.) Crystallization of the crude products afforded pure materials.

References:

[1] . Jacob, P., Anderson, S., Meshul, C., Shulgin, A. and Castagnoli, N., J. Med. Chem. 1977, 20, 1235.
[2a]. Heth-Cohn, 0. and Tarnowski, B., Synthesis, 1978, 56.
[2b]. Meyer, R.H., United States Patent Patent US3956395, May 11, 1976.
[3] . Although secondary and tertiary mercaptans provide excellent yields of the ortho-alkylthio substituted benzaldehydes with 2-bromobenzaldehyde, the use of the alkoxy substituted bromobenzaldehydes affords mixture of the desired products and dehalogenated starting materials. In the case of 4,5-methylenedioxy-2-bromobenzaldehyde (1d), cleavage of the methylenedioxy ether was the major pathway.
[4] . Ketones react in a similar fashion. Unpublished results from these laboratories.
[5] . Kametani, T., Hirai, Y., Kajiwara, H., Takahashi, T. and Fukumoto, K., Chem. Pharm. Bull., 1975, 23, 2634.
[6] . Pschorr, R., Liebigs. Ann. Chem., 1912, 291, 23.
[7] . Kametani, T., Teriu, T., Ozimo, T., and Fukumoto, K., J. Chem. Soc., (C), 1969, 874.
[8] . Dallacker, F., Liebigs. Ann. Chem., 1960, 603, 14.
[9] . Kametani, T., Takahashi, T., Ihara, H., Fukumoto, K., J. Chem. Soc., Perkin Trans. I., 1976, 389.
[10]. Brown, E. and Robin, J.P., Tetrahedron Lett., 1978, 3613.
[11]. Barfknecht, C.F. and Nichols, D.E., J. Med. Chem., 1971, 14, 370.
 
 
 
 
    catastrophe
(Hive Bee)
05-29-03 15:38
No 436416
      Nice Chimi!!!
(Rated as: excellent)
    

It was sooooo nice of you to type all of that up, thanks Chimi!smile That will most definetly work on all substituted halo-benzaldehydes. Sodium hydride, frown, ARGGHHH! SWIM can't get that, but possible alternatives are available. How about this...??

From Patent US2761873

Example 7
Preparation of p-methylmercaptobenzaldehyde
A solution of potassium methyl mercaptide in ethanol is prepared by dissolving 240 g. of potassium hydroxide in 2.5 liters of absolute ethanol and saturating this solution with methyl mercaptan.

525 g. of p-chlorobenzaldehyde is added to the potassium methyl mercaptide solution. The resulting mixture is refluxed as methyl mercaptan is bubbled into the mixture for a period of three hours. A precipitate of potassium chloride separates during the reaction.

The reaction mixture is diluted with water and extracted with CCl4. The extract is collected and distilled under reduced pressure. The desired product distills 99-100 C. at about 1.3 mm.


Well, that's nice but you may be saying, "No yield!??". Or maybe it was just SWIM, but now comes in another patent, Patent US5298630. SWIM will make comments in orange...

According to the check experiment carried out by the inventors of the present invention, the process (A) process (A) is Patent US2761873 stated above is disadvantageous in that as chlorobenzaldehyde is reacted with an alkanethiol in a homogeneous system, the alkanethiol tends to react with the active aldehyde group of the chlorobenzaldehyde to give by-products so that the yield of the object alkylthiobenzaldehyde is inevitably very low...

In view of this situation, the inventors of the present invention explored in earnest for proposing a process for producing alkylthiobenzaldehydes in an expedient and economical manner. As a result, they discovered that when a halobenzaldehyde of general formula (IV) is reacted with an alkanethiol of general formula (V) in the presence of a base and water in a heterogeneous phase as schematically shown below, the corresponding alkylthiobenzaldehyde of general formula (VI) is successfully obtained.

general formula IV = a halobenzaldehyde with the halogen being Cl or Br general formula V = an alkanethiol of the formula R3SH, where R3 means an alkyl group containing 1 to 4 carbon atoms. This alkyl group may be straight chained or branched
(2C-T-4). Such alkyl group includes, among others, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s-butyl, t-butyl and so on.

The halobenzaldehyde which is used as a starting material in the present invention includes, [bold]among others[/bold], 2-chlorobenzaldehyde, 2-bromobenzaldehyde, 4-chlorobenzaldehyde, 4-bromobenzaldehyde and so on.

The proportion of alkanethiol used is generally 0.8 to 3.0 mol equivalents and preferably 1.0 to 2.0 mol equivalents relative to the halobenzaldehyde...


They go on giving more options and restrictions on the reagents, you can read these for yourself. Let's get to the experimental...

Example 1

A four-necked flask of 200mL capacity, equipped with a stirrer, thermometer and reflux condensor, was charged with 11.2 g (0.28 mol) of sodium hydroxide and 80 g water under a nitrogen atmosphere and 13.5 g (0.28 mol) of methanethiol was bubbled through the charge at room temperature for about 1 hour to prepare an aqueous solution of the methanethiol sodium salt. To this aqueous solution was added 28.1 g (0.2 mol) of 2-chlorobenzaldehyde and the reaction was conducted in the presence of 1.1 g of tetra-n-butylammonium bromide (PTC) at 80 C for 4 hours. The reaction mixture was then cooled to room temperature and extracted with methylene chloride. The methylene chloride layer was separated, concentrated and distilled under reduced pressure to give 28.9 g of 2-methylthiobenzaldehyde (b.p. 116 - 118 C/5 mmHg). The yield based on 2-chlorobenzaldhyde was 95%

The procedure of Example 1 was repeated except that the halobenzaldehyde and alkanethiols shown in Table 2 were employed.

Table 2

Halobenzaldehyde          Alkanethiol         Alkylmercaptobenzaldehyde            Yield
----------------          -----------         -------------------------            -----
2-Chlorobenzaldehyde    Ethanethiol        2-Ethylthiobenzaldehyde                   92%
2-Bromobenzaldehyde    2-Propanethiol    2-Isopropylthiobenzaldehyde              90%
4-Chlorobenzaldehyde    Methanethiol     4-Methylthiobenzaldehyde                   96%
4-Chlorobenzaldehyde    Ethanethiol        4-Ethylthiobenzaldehyde                     93%
4-Chlorobenzaldehyde    1-Propanethiol    4-n-Propylthiobenzaldehyde                89%
4-Chlorobenzaldehyde    1-Butanethiol     4-n-Butylthiobenzaldehyde                  87%


But will it work for substituted halobenzaldehydes??? SWIM most definitely thinks so. Patent US5298630 is just an improvement on Patent US2761873, where they give a variety of compounds that this procedure will work on. And for you Chimi, SWIM made a note of the fact that they say it will work for branched alkanethiols too, great for 2C-T-4. With the article that you gave above, we may be close to getting them all cool

BTW methanethiol can be made by refluxing sodium methyl sulphate in a solution of sodium hydrogen sulphide who's synthesis is descibed by Rhodium here...Post 432858 (Rhodium: "Sodium Hydrogen Sulfide solution preparation", Chemistry Discourse)
 
 
 
 
    Chimimanie
(Hive Bee)
05-30-03 18:36
No 436683
      Little analysis of the dimethoxybenzaldehyde refs
(Rated as: excellent)
    

Catastrophe, you should look at the two articles at the same time.

The article I posted Post 435958 (Chimimanie: "Our old friend Poix", Chemistry Discourse) was published before ../rhodium/chemistry /4-alkylthio-25-dmb.html.

In fact this last article was a modification of the Synth. Commun. article, made by a spanish group.

From the spanish article at Rhodium's:


More recently a preparation Post 435958 (Chimimanie: "Our old friend Poix", Chemistry Discourse) was described of 2,5-dimethoxy-4-methyl-thiobenzaldehyde and its 4-benzylthio analog by nucleophilic substitution of 4-bromo-2,5-dimethoxybenzaldehyde in DMF with the respective sodium salts of methyl and benzyl mercaptane, This synthesis involves the preparation of the sodium mercaptides with NaH under nitrogen.

An easier way, with similar mechanistics to this last one seemed initially viable, general, and considerably shorter.




And they describe the same reaction using K2CO3 in place of sodium hydride:



...we found that the substitution of halogen atom of 4-bromo-2,5-dimethoxybenzaldehyde using thiols as nucleophiles in DMF and in the presence of K2CO3 takes place at room temp and it is practically complete in 48 hours. In this way we obtained the 4-ethylthio- (5), 4-propylthio- (6) and 4-(2-hydroxyethyl)- thio-2,5-dimethoxybenzaldehydes (7) with excellent yields.




...you dont need NaH, K2CO3 work well. That's the principal information to learn in this text.

Another info is that hydroxyethyl mercaptan can bee used too (useful for 2C-T-21 and 2C-T-13), as well as other N-alkyl (2C-T-2 and 2C-T-7).

We have got a nice general method for synthetizing 2C-T compounds, using easily avaiable chemicals (beside 2,5-DMB). Now we must consider its potential uses and its limitations.

The ref at rhodium dont tell us much about them. But the Synth. Commun. ref posted above tell us what we can do and what we can't:


-We must beware 0-dealkylation:



Thus a method for the synthesis of alkylthio substituted benzaldehydes which would accommodate the presence of alkoxyl substituents was investigated.




-We must have an aldehyde group on the ring to bee able to use this bromo -> thiol substitution. And, very important, it must be well situated vs the leaving bromine atom. We can only make ortho-alkylthio-benzaldehydes and para-alkylthio-benzaldehydes, from the corresponding ortho-/para- bromide. We cannot make meta-alkylthiobenzaldehydes:



The facile nature of this reaction is due presumably to the activation effect of the aldehyde group.[4] Aldehydes with bromine substituted in the para- position react similarly (see Table IV). However, aldehydes with bromine substituted in the meta- position to the carbonyl are unreactive under these conditions.




-We can't use methylenedioxy or 3,4,5 substituted benzaldehydes:



The low yields of the methylenedioxy substituted products 2d and 3d result from cleavage of the ether by the nucleophilic sulfur reagent. In the case of the sterically congested 2-bromo-3,4,5-trimethoxybenzaldehyde (1f), reaction with the sodium salt of methyl mercaptan is very slow and affords a 80% yield of unreacted aldehyde 1f with the remainder being dehalogenated aldehyde.




-And, more important, we cannot use secondary or tertiary mercaptan (at least not at the position 2)frown:



Although secondary and tertiary mercaptans provide excellent yields of the ortho-alkylthio substituted benzaldehydes with 2-bromobenzaldehyde, the use of the alkoxy substituted bromobenzaldehydes affords mixture of the desired products and dehalogenated starting materials. In the case of 4,5-methylenedioxy-2-bromobenzaldehyde (1d), cleavage of the methylenedioxy ether was the major pathway.




So even if it work in your patent, it will not work with methoxy substituted benzaldehydesmad.

And then, taken from the words of the authors, this is what I think of the method (I mean of the spanish variation of this method):



Although this method is limited to the use of primary mercaptans and sterically unhindered aldehydes, it offers a simple and efficient method for the preparation of oxygenated alkylthiosubstituted benzaldehydes from readily available precursor.




If you have access to 2,5-dimethoxybenzaldehyde that is.

Please note that we can make ortho- substituted benzaldehyde; for instance, the 4-alkylation of vanillin, then bromination to 2-bromo-4-alkoxy-5-methoxy-benzaldehyde, followed by treatment with a primary sulfide, will yield the 2-alkylthio-4-alkoxy-5-methoxy-benzaldehyde.

Sadly those 2-alkylthio analogues are probably not much potent, but if had to suggest one, maybe the 2-methylthio-4-ethoxy-5-methoxy-amphetamine would be interesting, as a thio analogue of MEM (BTW methyl sulfide can bee generated from dimethyl disulfide).

Please note also that we can debenzylate the benzylthio analogue, obtained in 95% (crystallized yield) from 4-bromo-2,5-DMB, and alkylate it with another alkyl group (secondary or tertiary will work here)smile.

As the compound is obtained in such a good yield, it looks like an attractive method for making all the 4-alkylthio-analogues we want with this route.

All we need to find is a debenzylation ref for it as well as a synth of benzyl mercaptan... Time to go at the librarylaugh....againwink!

 
 
 
 
    moo
(Hive Bee)
05-30-03 20:18
No 436699
      Cheers     

I have not much to contribute to this thread but great work you are doing. Making great finds in the library and getting into heavy brainstorming is life!

fear fear hate hate
 
 
 
 
    Rhodium
(Chief Bee)
06-01-03 17:29
No 437082
      Some precursors we haven't mentioned yet
(Rated as: excellent)
    

2,5-dimethoxythiophenol
Phosphorous, Sulfur and Silicon 68, 261-291 (1992)

To 0.84 g (34.5 mmol) magnesium turnings in dry THF, 7.5 g (34.5 mmol) of 2,5-dimethoxybromobenzene in 10 ml THF was added dropwise and the solution began to boil. After stirring at 20C for 3h the Mg was completely dissolved, and the solution was cooled to 0C. 1.1g elemental sulfur was then added slowly in small portions. After stirring for 1h at 0C, water was added and the solution acidified to pH 3. The 2,5-dimethoxythiophenol was extracted with DCM, the organic phase dried and evaporated. The residue was distilled at 80-85C/0.05mmHg to give 2.5g 2,5-dimethoxythiophenol (43%).

In conjunction with this prep, I should probably mention Post 413041 (Rhodium: "2,5-Dimethoxybromobenzene Grignards", Novel Discourse) and Post 354784 (Rhodium: "Tips & Tricks regarding dimethoxybenzene Grignards", Novel Discourse).


2,5-Dimethoxy-4-methylthiobenzaldehyde
Patent US4105695 Read this, and the references!

A solution of 6.07 g (0.33 mole) of 1,4-dimethoxy-3-methylthiobenzene in 40 ml of dry CH2Cl2 under N2 was cooled in an ice bath. To the solution was added 13.02 g (0.05 mole) of SnCl4 over 2 mins. Dichloromethyl methyl ether, 3.45 g (0.03 mole), was then added, dropwise, over 5 mins., and stirring was continued with ice bath cooling for 15 mins. The reaction was allowed to warm to room temperature over 30 mins. and was stirred for an additional 1 hr., at which time HCl evolution has ceased. The mixture was slowly poured onto 15 g of ice in a separatory funnel and the aqueous layer was separated and discarded. The organic phase was washed with 3 x 25 ml of 3N HCl, 3 x 25 ml of saturated NaCl solution, dried (Na2 SO4) and the solvent removed in vacuo. The solid residue was dissolved in CH3OH, and the solvent removed in vacuo. The solid residue was dissolved in CH3OH, filtered, and recrystallized from MeOH-H2O to give 5.86 g (92% ) of yellow needles. TLC  (silica gel-CHCl3) showed only one product. An analytical sample, further purified via the NaHSO3 adduct and recrystallized from MeOH-H2O, had a mp of 99-100C.
1H NMR (CDCl3) 2.48 (s, 3H, SCH3), 3.92, 3.97, (2s, 6H, OCH3), 6.74, 7.29 (2s, 2H, ArH), 10.45 ppm (s, 1H, CHO).


Also, another route to thiophenols, which I think we have overlooked in our recent discussions: Post 207554 (Antoncho: "An easy OTC 2,5-diMeO-phenylmercaptan", Novel Discourse)
 
 
 
 
    Rhodium
(Chief Bee)
07-19-03 16:18
No 448501
      Aromatic Thiols by Electrophilic Substitution
(Rated as: excellent)
    

Facile Introduction of SH Group on Aromatic Substrates via Electrophilic Substitution Reactions
J. Org. Chem. 68, 5758-5761 (2003) (../rhodium/pdf /arylthiol.eas.synth.pdf)
DOI:10.1021/jo034013h

Abstract

Herein, we describe a mild and efficient two-step procedure to introduce a thiol group on aromatic substrates.
First, reaction with bis-(2-Methoxycarbonyl-ethyl)sulfoxide (from the double michael addition of methyl acrylate to NaSH, followed by NaIO4 oxidation of the formed thioether to the sulfoxide, 90% overall yield) leads to an arylsulfonium salt intermediate. Then, two successive beta-elimination-based dealkylation reactions (Et3N and/or t-BuOK in THF) afford the desired arylthiols in good to excellent yields (usually 70-90% yield).




Sulfuration of organoborates, an underexploited method
Tetrahedron Letters 41(32), 6053-6057 (2000) (../rhodium/pdf /sulfuration.organoborates.pdf)
DOI:10.1016/S0040-4039(00)00945-X

Abstract

The combination of sulfurating agents with organoboranes is an underexploited synthetic transformation.The reactivity of borate complexes was investigated with several electrophilic sulfur species, such as S2Cl2, ditosyl sulfide and elemental sulfur. Simple and practical methods for making carbonsulfur bonds were created under almost neutral conditions. These enjoy a heavy metal-free environment and use not so toxic boron compounds. This is in contrast to the manipulation of poisonous H2S or the use of sulfur with Grignard reagents, under highly basic and moisture-sensitive conditions.
 
 
 
 
    imp
(Stranger)
10-16-03 21:31
No 465112
      Nice Article     

From Post 433179 (catastrophe: "Aralkyl halides to Thiols", Chemistry Discourse).

The ref. : H.-L. Pan and T.L. Fletcher, Chem. Ind., 546(1968) has been retrieved and reads as follows...


Dimethyl sulphoxide (DMSO) has been found to greatly facilitate many reactions, especially displacement reactions of alkyl or aryl halides with anions. We now find further confirmation of this unique property of DMSO in the ease of formation of sulphydryl compounds from reactions between aralkyl halides and thiourea. Fluoren-9-thiol was prepared in quantative yields by reacting 9-bromofluorene and thiourea in DMSO, followed by alkaline hydrolysis, all at room temperature and in one continuous operation. Likewise, p-bromobenzylthiol and p-methylbenzylthiol were prepared in near quantative yields from the corresponding aralkyl bromides in DMSO. There is no oxidation of the thiols under these conditions.

In a typical run, 9-bromofluorene (0.1 mole) and thiourea (0.11 mole) were magnetically stirred overnight in DMSO (150 ml.) at room temperature in an open flask, then poured into 10 per cent aqueous sodium hydroxide (600 ml.). Stirring was continued for 30 minutes and the mixture was acidified with dilute hydrochloric acid. The product, fluoren-9-thiol, (19.6 g., 99 per cent) thus obtained melted at 103-106 C (reported mp 105-106). The 9-thio-acetate derivative melted at 78.5-79 C. In the reaction as usually run, the isothiuronium salt was isolated after preparation from 9-bromoflourene and thiourea in refluxing butan-1-ol. Hydrolysis of the isothiuronium salt in boiling aqueous alkali, under N2, affored the 9-sulphydryl compound in considerably lower yields. However, when treated with isothiuronium bromide, so prepared, with 5 per cent sodium hydroxide in DMSO at room temperature for 15 minutes, a 96 per cent yield of pure fluoren-9-thiol was obtained. p-Bromobenzylthiol (mp 25-27 C) was prepared from p-bromobenzylbromide as described above (total time, 1.5 h) in 97-100 per cent yields. Likewise, p-methylphenylthiol was obtained in 86 per cent yield from alpha-bromo-p-xylene.

This facile preparation should be additionally valuable when heat sensitive or otherwise highly reactive compounds are involved. Oxidation of the sulphydryl group does not occur in the preparation.

 
 
 
 
    Rhodium
(Chief Bee)
10-25-03 16:54
No 466763
      Aryl sulfur compounds by photo-rxn w/ thiourea
(Rated as: good read)
    

One-Pot Two-Step Synthesis of Aryl Sulfur Compounds by Photoinduced Reactions of Thiourea Anion with Aryl Halides
Juan E. Argello, Luciana C. Schmidt, and Alicia B. Peory
Organic Letters 5(22), 4133-4136 (2003) (../rhodium/pdf /arylthiols.photo-thiourea.pdf)
DOI:10.1021/ol035545n



Abstract

The photoinduced reactions of aryl halides with the thiourea anion afford arene thiolate ions in DMSO. These species without isolation, and by a subsequent aliphatic nucleophilic substitution, SRN1 reaction, oxidation, or protonation, yield aryl methyl sulfides, diaryl sulfides, diaryl disulfides, and aryl thiols with good yields (50-80%). This is a simple and convenient approach which involves the use of the commercially available and inexpensive thiourea in a one-pot two-step process for the synthesis of aromatic sulfur compounds.
 
 
 
 
    Rhodium
(Chief Bee)
09-30-04 04:09
No 533895
      Grignard synthesis of 4-Methoxybenzenethiol
(Rated as: excellent)
    

4-Methoxybenzenethiol
J. Szmuszkovicz
Org. Prep. Proced. Int 1(1), 43-45 (1969)

We would like to bring to your attention a convenient and efficient procedure for the preparation of 4-methoxybenzenethiol by the treatment of p-methoxyphenylmagnesium bromide with sulfur1, which has been overlooked in the literature in preference to other methods. Thus, 4-methoxybenzenethiol has been prepared by reduction of p-methoxyphenylsulfinic acid with zinc2; by reduction of p-methoxyphenylsulfonyl chloride with zinc3, tin4, red phosphorus and iodine5, or by electrolytic reduction6; and by diazotization of p-anisidine followed by treatment with potassium ethyl xanthate and alkaline hydrolysis.7

Experimental

p-Methoxyphenylmagnesium bromide

A 5000 mL, three neck, round bottom flask, equipped with a condenser, thermometer, addition funnel and air-stirrer, was flame dried under nitrogen. Magnesium (38.8; 1.6 mole) was placed in the flask and covered with ether. One crystal of iodine was added, then about 20 ml of a solution containing 300g (1.6 mole) of p-bromoanisole in 1600 ml. of ether. Reaction started in a few minutes and the mixture was then stirred and refluxed while the rest of the above solution was added during about 1.5 hr. After the addition was completed, the mixture was refluxed for 1 hr.

4-Methoxybenzenethiol

The above mixture was cooled to 30C. Solid sulfur (46.4 g; 1.45 mole) was added portionwise over 30 min. with only occasional cooling so that the temperature was 30-35C. The mixture was then stirred for 1 hr. at room temperature, cooled to 0C with a methanol-ice bath and decomposed by slow addition of 1600 ml. of 2.5 N hydrochloric acid keeping the temperature below 5C. The organic layer was separated8 and extracted with 2 N sodium hydroxide (5 x 200 mL). The basic extract was cooled in ice and acidified with 650 mL of 10% hydrochloric acid (check pH). The product was extracted with ether (4 x 200 ml.). The ether extract was washed with 200 ml. of saturated sodium chloride solution, dried (MgSO4) and evaporated to give 134g of residue. Distillation through a 15 cm Vigreux at 13 mmHg gave 110.6 g. (49% yield) of an oil boiling at 100-103C (no forerun, some pot residue present).

λmaxEtOH 239 mµ (10,000); 285.5 (1,300), sh 291 (1,250);vmaxNujol SH: 2560; C=C: 1590, 1570, 1490; C-O: 1285, 1240, 1180, 1175, 1030; aromatic: 820, C-S: 635, 625. NMR (CDCl3 solution, 60-Mc, tetramethylsilane): SH singlet at 201 cps, area 1; OCH3 singlet at 244 cps, area 3; aromatic = typical para substituted pattern centered at 408 and 437 cps.

References

[1] This procedure was reported briefly without experimental details by M. F. Taboury, Bull. Soc. Chim. France, [3] 33, 836 (1905)
[2] L. Gatterman, Ber., 32, 1136 (1899)
[3] Y. Schaafsma, A. F. Bickel and E. C. Kooyman, Rec. Trav. Chim., 76, 180 (1957);
L. Almasi, A. Hantz, and L. Paskucz, Acad. Rep. Populare Romine, Filiala Cluj., Studii Cercetari Chem., 12, 165 (1961);
M. Protiva, M. Rajsner, E. Adlerova, V. Seidlova and Z. J. Vejdelek, Collection Czech. Chem. Commun., 29, 2161 (1964)
[4] W. L. Nobles and B. B. Thompson, J. Pharm. Sci., 54, 709 (1965)
[5] A. W. Wagner, Ber., 99, 375 (1966)
[6] F. Fichter and W. Tamm, Ber. 43, 3032 (1910)
[7] C. M. Suter and H. L. Hansen, J. Am. Chem. Soc., 54, 4100 (1932);
V. N. Vasileva and E. N. Guryanova, J. Gen. Chem. USSR (Engl. Transl.) 26, 777 (1956);
E. E. Campaigne, J. Tsurugi and W. W. Mayer, J. Org. Chem., 26, 2486 (1961)
[8] Dissemination of bad odor can be avoided by working in a good hood without spilling and letting all the used equipment soak in 5% sodium hydroxide solution overnight.

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