[Bishounen]

Hi guys ! I have this problem and hoped you could please help me ^_^
It's about the synthesis of metolazone, a diuretic drug.
I have the chain of reactions that lead to it but i need the mechanism of reaction for each reaction. A total of 6 reactions ^_^
I shall post a picture of the reaction scheme. Please if there is anyone that has some free time to sketch up the mechanism i would really appreciate it ANd the faster...the better THANK YOU !

[StarvinMarvin]

You see, the way things work around here is that you have to show that you tried. It's not about doing someone's homework - it's about learning. So, let us start from the first reaction - do you have any idea how such reaction might proceed?

Find a nucleophile in the first reaction and show how it would react.

[Bishounen]

Sorry it was rude of me to ask it like that
Thank you for trying to help me
I think that this might be correct for the first reaction
Is this correct? please tell me if it is not ... i will try working on the others could you give me a hint about what kind each of the reaction is since it helped for the first one
thank you

[StarvinMarvin]

The mechanism looks OK to me.

The second reaction is a two-step reaction. First, try to draw the reagents and again find nucleophile and electrophile that would be susceptible to attack.

[Bishounen]

i am having problems with the second reaction with the chlorosulfonic acid
i thought the O bonded to the H in the ClSO3H would be bonded to the C atom in the cycle...but it would result a O-SO2Cl not a -SO2Cl compund....what am i doin wrong?

[StarvinMarvin]

Draw the chlorosulfonic acid structure. As you know, the double bond will attack in this mechanism. When you draw the structure, you'll know where. Can you tell?

[Bishounen]

Well it's obvious from the result that it should bind to the S atom
but i don't know why...i thought about sulfuric acid and since the only different thing between their structures is that instead of -OH it has -Cl...so i assumed the O would be the more electronegative one and it would bind from there....
And also....when doing the third reaction with ammonia...why does it only attack the -Cl that binds SO2?
thank you !!!

[StarvinMarvin]

It's obvious not only because of the resulting structure. Consider the electronegativities of sulfur and oxygen. The electron density is withdrawn from the sulfur atom making it a vulnerable place for attack.

Edit:

Ammonia doesn't attack Cl atom. It attacks, once again, the sulfur. Cl is just a leaving group.

[Bishounen]

i reached reaction number 4
is there an exact mechanism to the oxidation with permanganate?
also a question regarding reaction 5...why is there a cyclization? what goes on?? help !
thank you

[StarvinMarvin]

I'll be honest with you: I did not find actual mechanism for KMnO4 oxidation of aromatic methyl groups that would validate my own ideas. I would thik, though, that MnO4- acts similarly to OsO4 (in diol synthesis) and utilizes a fact that benzylic positions are more reactive than a regular alkane thus undergoing oxidation in a similar manner.

As far as the cyclization is concerned:

To get it sorted out first think, how SOCl2 react with the starting material. Then try to draw partial charges on the protected amine. I think you will figure it out on your own when you do that.

[Arctic-Nation]

Now this is a nice thread.

Just posting to say that I don't think a mechanism for the oxidation of aromatic methyl groups by permanganate is known. I've never been taught one, standard textbooks don't mention one, and I believe that if a chemist tells you he knows one he's probably only telling part of the story.

About reaction number 5: this one's rather difficult, as it involves the formation of an aminal ether, a carbon atom bearing both (single-bonded) oxygen and nitrogen atoms. Once you figure out how to form that, its further reactions should become clear.

[orgopete]

The mechanism looks OK to me.

The second reaction is a two-step reaction. First, try to draw the reagents and again find nucleophile and electrophile that would be susceptible to attack.

While that succeeds in arriving at the final product, I am unhappy with chloride being the base rather than the more basic aniline or another base that might have been used but omitted from the scheme.

[StarvinMarvin]

Well, usually such reactions are performed in the presence of a base :pyridine, imidazole or more likely K2CO3 which are supposed to deprotonate the quaternary amine and catch the leaving Cl-. This mechanism is OK in principle, though.