Sciencemadness Discussion Board - Synthesis of bourgeonal

Synthesis of bourgeonal

Lambda-Eyde - 14-2-2012 at 21:45

Bourgeonal is very interesting despite being a structurally simple compound. Human sperm is attracted to the compound, causing them to swim faster, so it is suspected to play a role in human reproduction. Also, males have on average a higher sensitivity to the smell of the compound which is remniscient of Lily of the Valley. That's enough of a reason to synthesize it, IMO.

My proposed reaction scheme is shown below. I'd like you to point out any flaws you might see in regard to the order of the reactions and methodology. Would it be wiser to t-butylate after the grignard, is it OK the way I've done it, or doesn't it matter at all? I see now (after drawing and uploading the reaction scheme) that t-butylating bromobenzene wouldn't probably give a high regioselectivity (p-substitution being what I'm after). Another solution would perhaps be to do the grignard first, and then the FC-alkylation.

For the oxidation of the alcohol to the aldehyde, I'm considering using pyridinium chlorochromate (PCC). The reason I've omitted it from the scheme is because I haven't checked reaction conditions yet.

Reaction scheme:

Bromobenzene is alkylated with t-butyl chloride in the presence of AlCl3, giving primarily the p-substituted benzene. The alkyl chloride is easily prepared by the reaction of aqueous HCl with tert-butanol.[1] The substituted bromobenzene is then reacted with magnesium turnings in anhydrous diethyl ether giving the grignard reagent. This is then reacted with oxetane (1,3-propylene oxide) giving 3(4-t-butylphenyl)propanol upon aqueous workup.[2] This can be oxidized with a mild oxidizing agent such as PCC giving the target compound, bourgeonal.

Oxetane itself can be prepared relatively easily in a three-step synthesis starting with 1,3-propanediol. 1,3-propanediol is gassed with dry HCl at 160 oC, giving 3-chloro-1-propanol (trimethylene chlorohydrin) in 50-60% yield. A large portion of unreacted alcohol can be recovered. [3] This is then converted to the acetate ester by reaction with glacial acetic acid plus an acid catalyst in benzene. By the use of a Dean-Stark trap, a yield of 93-95 % is achieved.[4] One could probably substitute the benzene for toluene, as both form an azeotrope with water which separate on cooling. I prefer to say "use toluene where you can, and benzene when you must".

The 3-chloropropyl acetate is then heated with KOH and water, giving oxetane in 42-44 % yield.[5]

I don't have propanediol on hand, though. My local supplier carries it at unbelievable prices which makes it hard to believe they spray airplanes with the stuff... However, I remember seeing some discussion on the subject in an earlier thread which I will look up when I have time. If someone knows of a European supplier that'd be willing to sell 0,5-1 L for a reasonable price I'd be happy to know.

Comments, criticism and general thoughts are welcome.

References:

1. Vogel's, 5th ed. p. 556
2. Searles, J. Am. Chem. Soc., 73, 124 (1951) (Note: I haven't had a look at this article yet, but it is mentioned in this orgsyn prep.)
3. Organic Syntheses, Coll. Vol. 1, p.533 (1941)
4. Organic Syntheses, Coll. Vol. 3, p.203 (1955)
5. Organic Syntheses, Coll. Vol. 3, p.835 (1955)

benzylchloride1 - 14-2-2012 at 22:34

Another possibility would be to run a Kumada-type coupling of allyl magnesium bromide with 4-bromo-tert-butylbenzene to get 4-tert-butylallylbenzene. This could be hydroborated with diborane generated in situ and then the resulting organoborane oxidized to get the corresponding alcohol, which could finally be oxidized to the desired aldehyde. Several methods for generating diborane are described in Advanced Organic Synthesis by Richard S. Monson.

[Edited on 15-2-2012 by benzylchloride1]

UnintentionalChaos - 14-2-2012 at 23:21

I don't think that the first step is going to go very well, since the aromatic ring is deactivated by the bromine. Using it after the grignard might raise issues due to complexation of the lewis acid with the alcohol.

If you could somehow put together 4-tertbutylaniline (mononitrate tert-butylbenzene and reduce?), you could Sandmeyer it to the aryl halide (1) and proceed from there.

Alternately, subject the tert-butylbenzene to a duff formylation in TFA (probably a sticking point) giving a 75% yield of p-tertbutylbenzaldehyde (2) Now you have a few options...

1) make and reduce a 4-tertbutylcinnamate ester via the Bouveault–Blanc reduction, concurrently reducing the alpha-beta unsaturation to give the 3-arylpropanol. (see discussion and references in (3)). Options for cinnamic acid: Perkin reaction, Knoevenagel condensation (acid hydrolysis of dialkyl malonate product or base hydrolysis of alkyl acetoacetate product). You will need to esterify the product, probably by Fischer esterification. The alcohol can be oxidized to the aldehyde by say, PCC/PDC, DMP, etc. in DCM. Chromate and hypervalent iodine compounds are good bets here as is a swern oxidation

2) make the cinnamic acid as above. Electroreduce to the dihydrocyannamic acid (4). Esterify. DIBAH will furnish the aldehyde product directly

3) Use Ph3P=CH2 to turn the benzaldehyde into the styrene (wittig). Use the procedure in the paper that mentions your reference 2 to make the 4-aryl-m-dioxane. Reduce to the alcohol as described in (3). Oxidize as described above.

I am sure there are other approaches, but I am tired.

1) http://www.orgsyn.org/orgsyn/prep.asp?prep=cv1p0136
2) J. Org. Chem. 37(24), 3972-3973 (1972) (http://www.erowid.org/archive/rhodium/chemistry/formylation....)
(3) http://www.orgsyn.org/orgsyn/prep.asp?prep=cv4p0798
(4) http://www.orgsyn.org/orgsyn/prep.asp?prep=cv1p0311

[Edited on 2-15-12 by UnintentionalChaos]

Ebao-lu - 15-2-2012 at 09:00

There is some information on alkylation of aniline with t-butanol and methyl-t-butyl ether in google, maybe you can find a catalyst and conditions that give a satisfactory yield of 4-t-butylaniline. Then acylate the resulting mixture with acetic acid or acetic anhydride and isolate acylated 4-t-butylaniline via acid-base extraction(for example) because it should be acylated faster (or at milder conditions) then other isomers (N-alkylated, 2-alkylated, dialkylated), followed by separation from unreacted aniline usind different solubility in water or some ionic salt water solution
Also there is some information that Meerwein arylation can be carried out with acrolein. Then you need to eliminate HCl from 2-chloro-3-arylpropanal and then reduce the double bond (Mg/EtOH?), also you can get 2-SCN-3-arylpropanal if you carry out Meerwein arylation in the presence of KSCN and then SCN can be hopefully removed by Ni raney.

Instead of oxetan in grignard reaction you can try to use acrolein, maybe in the presence of Cu salts to prevent carbonyl addition(not sure), or if it not works, i'm sure i have seen some paper on making acetal of 3-halopropanal from acrolein, some alcohol(methanol i suppose) and either HBr or HCl, i think it should yield a desired compound in grignard reaction

[Edited on 15-2-2012 by Ebao-lu]

[Edited on 15-2-2012 by Ebao-lu]

Lambda-Eyde - 15-2-2012 at 18:44

Quote: Originally posted by benzylchloride1

Another possibility would be to run a Kumada-type coupling of allyl magnesium bromide with 4-bromo-tert-butylbenzene to get 4-tert-butylallylbenzene. This could be hydroborated with diborane generated in situ and then the resulting organoborane oxidized to get the corresponding alcohol, which could finally be oxidized to the desired aldehyde. Several methods for generating diborane are described in Advanced Organic Synthesis by Richard S. Monson.

The hydroboration route sounds really interesting. I'm interested in organometallic chemistry and metal-catalyzed organic reactions. I don't have any Pd at hand, but I do have plenty of nickel salts, so this is certainly not out of the question. Making a batch of allyl alcohol per orgsyn (and some derivatives) are on my to-do list as well.

Quote: Originally posted by UnintentionalChaos

I don't think that the first step is going to go very well, since the aromatic ring is deactivated by the bromine. Using it after the grignard might raise issues due to complexation of the lewis acid with the alcohol.

I should have thought of the deactivating effect of the halogen. I don't immediately think of them as ring deactivators, in my head it's mostly carboxyl and nitro groups I deem deactivating. Alkylating benzene and then brominating the product would make more sense.

Quote: Originally posted by UnintentionalChaos

If you could somehow put together 4-tertbutylaniline (mononitrate tert-butylbenzene and reduce?), you could Sandmeyer it to the aryl halide (1) and proceed from there.

Why couldn't I just subject t-butylbenzene to electrophilic substitution with bromine? I don't see why I'd want to do a Sandmeyer on such a simple molecule where I could easily add a bromine at the 4-position with one reaction step instead of three.

Quote: Originally posted by UnintentionalChaos

Alternately, subject the tert-butylbenzene to a duff formylation in TFA (probably a sticking point) giving a 75% yield of p-tertbutylbenzaldehyde (2) Now you have a few options...

Yes, that's the sticking point - TFA is horribly expensive. Also, I considered starting with benzyl alcohol. Making the chloride and reacting the grignard reagent with ethylene oxide would give 3-phenylpropanol. However, I found out that placing the t-butyl group in the p-position would be complicated when starting with benzyl alcohol.
Also, ethylene oxide is even more expensive than TFA and much, much more evil than oxetane. So I want to avoid it by all means.

Quote: Originally posted by UnintentionalChaos

The alcohol can be oxidized to the aldehyde by say, PCC/PDC, DMP, etc. in DCM. Chromate and hypervalent iodine compounds are good bets here as is a swern oxidation

I have papers on alcohol oxidations with PCC/PDC on my computer which I will go through when I have time. I don't think I'll go with DMP/IV for this one - as I understand, the virtue of these reactions are their tolerance for fragile functional groups (as well as their mildness), so I don't see the need to use them on a molecule which is just a hydrocarbon besides the targeted group.

Your other suggestions are very interesting, and I'd like to try many of those reactions in the future. But for this compound, adding a lot of reaction steps would just complicate everything and (not least!) diminish yields severely. Thanks for the references, by the way.

Quote: Originally posted by Ebao-lu

Instead of oxetan in grignard reaction you can try to use acrolein, maybe in the presence of Cu salts to prevent carbonyl addition(not sure), or if it not works, i'm sure i have seen some paper on making acetal of 3-halopropanal from acrolein, some alcohol(methanol i suppose) and either HBr or HCl, i think it should yield a desired compound in grignard reaction

I don't want to do any business with acrolein. Too toxic, lachrymatory and smelly for my taste. Your other suggestions are interesting but quite complicated.

UnintentionalChaos - 15-2-2012 at 19:04

Quote: Originally posted by Lambda-Eyde

You require lewis acid catalyst and generate HBr doing this. This is a situation ripe for trans-FC-alkylation as the t-butyl group is very labile relative to say, methyl.

Nitration introduces a deactivating group and halts as the mononitro product if kept cool. The product should be overwhelmingly para due to the bulk of the t-butyl group. Reduction and Sandmeyer are both fairly high yielding and clean.

The other suggestions were merely that, suggestions. The oxetane seems like a cool thing to make. You might want to read the notes for that orgsyn prep. You can go at reduced yield directly from the 3-chloropropanol, avoiding the formation of the acetate. Perhaps this will not save yield, but it will save time. If you get yourself a liter of 1,3-propanediol, what does a little bit matter

[Edited on 2-16-12 by UnintentionalChaos]

ThatchemistKid - 15-2-2012 at 20:48

I do not have much experience with FC-alkylation. Bromine is weakly deactivating but still ortho/para directing so this suggests that you can get the isomer that you desire via FC-alkylation of bromo-benzene you will just have to subject the reaction to harsher conditions, though to be honest the size of the t-butyl group might pose an issue. What I really am here to say is that there is no reason really to go through the oxatane or a lot of those round about methods mentioned. if you are using phenyl magnesium bromide you can just react it with acrolein using a catalytic amount a copper(I) halide (3% mole is good enough sometimes) and this causes 1,4 addition of the grignard reagent to the acrolein affording your product. the acrolein can be made easily by modification of the allyl alcohol orgsyn prep that was mentioned earlier if the temperature is allowed to climb past I believe it was 250 C large amounts of acrolein are formed.

[Edited on 16-2-2012 by ThatchemistKid]

UnintentionalChaos - 15-2-2012 at 20:51

Quote: Originally posted by ThatchemistKid

I do not have much experience with FC-alkylation. Bromine is weakly deactivating but still ortho/para directing so this suggests that you can get the isomer that you desire via FC-alkylation of bromo-benzene you will just have to subject the reaction to harsher conditions, though to be honest the size of the t-butyl group might pose an issue. What I really am here to say is that there is no reason really to go through the oxatane or a lot of those round about methods mentioned. if you are using phenyl magnesium bromide you can just react it with acrolein using a catalytic amount a copper(I) halide (3% mole is good enough sometimes) and this causes 1,4 addition of the grignard reagent to the acrolein affording your product. the acrolein can be made easily by modification of the allyl alcohol orgsyn prep that was mentioned earlier if the temperature is allowed to climb past I believe it was 250 C large amounts of acrolein are formed.

[Edited on 16-2-2012 by ThatchemistKid]

You do know that they have an acrolein prep as well, right?

ThatchemistKid - 15-2-2012 at 20:56

did not even cross my mind, I only said that because that is how I unintentionally made my acrolein, let my first attempt at their allyl alcohol synthesis get too hot because I did not have a suitable thermometer.

benzylchloride1 - 15-2-2012 at 22:58

Here is a prep of p-tert-butylbromobenzene:
In a 3-liter, three-necked flask equipped with a mechanical stirrer, dropping funnel
and reflux condenser leading to a trap for absorption of
hydrogen bromide, were placed 375 g. of t-butylbenzene
and 5 g. of iron powder. The mixture was stirred and
cooled by an ice-bath to 0-5". From the dropping funnel
was added, over a period of one to two hours, 500 g. of
bromine. Stirring was continued for two hours after all
the bromine had been added. The reaction mixture was
allowed to stand overnight and then washed with 5%
sodium sulfite solution, twice with 5% sodium carbonate
solution, twice with water and dried over calcium chloride.
The product was distilled from a modified Claisen flask
and collected at 80-81C (2 mm.). The yield of p-bromo-t-butylbenzene was 444 g. (75%).
J. Am. Chem. Soc., 1944, 66 (6), pp 914–918
See Vogels practical Organic Chemistry for the preparation of tert-butylbenzene via the Friedel-Crafts alkylation of benzene with tert-butyl chloride using either FeCl3 or AlCl3 as a Lewis Acid catalyst.

[Edited on 16-2-2012 by benzylchloride1]

UnintentionalChaos - 15-2-2012 at 23:01

Quote: Originally posted by benzylchloride1

Here is a prep of p-tert-butylbromobenzene:
In a 3-liter, three-necked flask equipped with a mechanical stirrer, dropping funnel
and reflux condenser leading to a trap for absorption of
hydrogen bromide, were placed 375 g. of t-butylbenzene
and 5 g. of iron powder. The mixture was stirred and
cooled by an ice-bath to 0-5". From the dropping funnel
was added, over a period of one to two hours, 500 g. of
bromine. Stirring was continued for two hours after all
the bromine had been added. The reaction mixture was
allowed to stand overnight and then washed with 5%
sodium sulfite solution, twice with 5% sodium carbonate
solution, twice with water and dried over calcium chloride.
The product was distilled from a modified Claisen flask
and collected at 80-81C (2 mm.). The yield of p-bromo-t-butylbenzene
was 444 g. (75%).
J. Am. Chem. Soc., 1944, 66 (6), pp 914–918

Shows you where speculation will get you....consult the literature before talking out your ass.