[rcheung]

Any suggestions on ways to synthesize a secondary amine from the primary without overalkylating?  Details are helpful: preferred solvents, temperatures, reagents, etc.  Also, what's a good way to perform separation on compounds like the amines which tend to streak on silica gel? Thanks.

[DaveD]

A common way to accomplish the synthesis of a secondary amine without overalkylating is to conduct a reductive amination reaction (sometimes referred to as a reductive alkylation reaction).  The primary amine is treated with an aldehyde in a solvent such as dichloromethane, sometimes in the presence of a dehydrating agent like Na2SO4, MgSO4, or in difficult cases TiCl4, to yield an imine.  This transformation can be easily monitored by 1H NMR if the reaction is done in an NMR tube in CD2Cl2.

One the imine has formed, there are a number of ways to reduce this to the target secondary amine; the most common are catalytic hydrogenation with a Pd or Pt catalyst, or by using sodium triacetoxyborohydride as the hydride source.

For your chromatography question - I have added low levels of TEA (about 1/2% by volume) to the eluent.  This often minimizes/eliminates the streaking.  But you have to make sure your molecule is stable to TEA before trying this :-)

[CDW101057]

A feasible way is to protect the amine (using Cbz or Ts) first and then to alkylate (followed by deprotection).

[Custos]

DaveD's suggestion of reductive amination using an aldehyde and reducing agent (sodium borohydride or sodium cyanoborohydride also work well in some cases) is the most common. Another way that is quite flexible is to use the Mannich reaction using your amine, aldehyde and benzotriazole. Carry out the reaction in a Dean-Stark trap with toluene to remove water (trace of trifluoroacetic acid helps). Isolate the product and then remove (borohydride) or displace the benzotriazole with a Grignard reagent. This is a method popularised by Katritzky - try looking up a review on benzotriazole if you're interested.

[Chudasama]

one possible way....

1) primary amine + acyl chloride (in the presence of base (usually NEt3)) = amide
 
    amide + LiAlH4 = secondary amine

[HP]

Another one:
R-NH2 + R-MgBr--> R-NHMgBr
R-NHMgBr + R2X --> RNHR2
Though i am not sure if amines react stoich with 1:1 mole ration with Grignard reagents : i mean its may be possible R-N(MgBr)2 side product  in minor yeld

[Custos]

Another one:
R-NH2 + R-MgBr--> R-NHMgBr
R-NHMgBr + R2X --> RNHR2
Though i am not sure if amines react stoich with 1:1 mole ration with Grignard reagents : i mean its may be possible R-N(MgBr)2 side product  in minor yeld

No that's not going to work. As the product RNHR2 is formed a competing side reaction will reaction of the product with R2X. That actually the problem with direct alkylation of primary amines - as the secondary amine is formed it also competes for any alkylhalide and secondary amine are more nucleophilic then primary so that reaction goes faster. If you have a 1:1 mixture of primary amine and RX you therefore end up with a mess of unreacted primary amine, secondary amine, tertiary amine and possibly even some quaternary amine.

In you suggested reaction the Grignard reagent is just going to act as a strong base - so it's no different from using (for example) LDA.

The other suggestion of making the amide and reducing with LiAlH4 will work, but is limited to making amines where one of the alkyl groups has a methylene of course.

[HP]

Well i am still not sure that the mechanism of Hoffman alkylation of amines is the same as RNHMgX + R-X  If reaction mixture 1:1 RMgX and well-reactive R-I for example then i think the reaction of secondary amine formation will be fast at low temperatures and kinetically much prefer than attack to NH group (with MgX). Of course as the reaction proceed then the product of reaction - secondary amine could react with still unreacted R-X but if the first reaction is fast enough then i think the predominant product (may be over 90%) will be desired 2amine...
One another sugestion for secondary methylamine based on Hoffman isonitrile reaction
R-NH2 + CHCl3 + 3KOH/EtOH --> R-N=C:
R-N=C: + H2 --> R-NHCH3

[HP]

One more hint: direct Michael addition of amine with alkenes. This reaction is catalyzed by some Rutenium transition methal complexes.
R-NH2 + CH2=CH-CH3 -->RNHCH(CH3)2 + RNHCH2CH2CH3(minor)
Very easy Michael addition of primary amines with activated double bond comp like acrylic acid or acrylonitrile:
R-NH2 + CH2=CH-COOH --> R-NHCH2CH2COOH (you'll say how to decarboxylate it
R-NH2 + CH2=CHCN--> R-NHCH2CH2CN+ H2--> RNHCH2CH2CH2NH2 +NaNO2/HCl--> (i cant remember now if secondary amines are stable in diazotation reaction...

[rcheung]

To reduce an imine to the secondary amine, what specific Pd or Pt catalysts are used?  After reduction, what is the easiest way to remove the catalyst from the reaction mixture?

Also, what's the difference between the different borohydride-based reducing agents?  If I decided to reduce using a borohydride reagent rather than using Pd or Pt catalysts, what's the easiest way to remove the borohydride reagent from the reaction mixture?

Thirdly, my compound also has a disulfide.  If I use a borohydride reagent, the disulfide will be reduce in addition to the imine.  Will the disulfide reduce if I use a Pd or Pt catalyst?  Are there other reducing agents I could use which will reduce the imine but not the disulfide?

Lastly, can someone offer a detailed explanation why a secondary amine can be a better nucleophile than a primary amine?  What are examples when this is the case and what are examples when this is not true?  Thanks for all of your *delete me*

[movies]

Sulfides often poison Pd or Pt catalysts (especially Pd), so that might not be a good choice.

[HP]

Hi,
I do correction to my previous post about Michael addition reactions of amines: overalkylation can't be 100% avoided by these routes as you can see - sorry for the mistake and may be only the first example with propylene addition to amine will give 100% yeld of secondary isopropyl derivate because the steric hindrance of the 2nd amine group by 2 CH3 groups even if propylene is in excess. Also tosylates could be used as reliable catalyst for this addition insted of more exotic Ru-cat...
Have you think aboud Maillard reaction of amines with sacharides  http://en.wikipedia.org/wiki/Maillard_reaction
The proposed schemes give only 2nd amine derivates of this type reactions. Its interesting what you think about post synthesis procedures for making the obtained by this teaction aduct to alkyl derivate 

[rcheung]

From what it sounds like, I should synthesize the imine first (without a disulfide present) and then oxidize using iodine to form the disulfide in a later step.  How is iodine typically removed from the mixture?  Any other suggestions on reagents to use for oxidizing thiols to the disulfide?

[Custos]

It depends on your thiol of course but sometimes just bubbling air through your solution can be enough to oxidise to a disulfide. Nice and clean when it works! Another way might be to use a mild oxidant like dilute bleach.

[movies]

Bleach might over oxidize to the sulfoxide or sulfone.  That is why bleach is so good at removing the thiol stench from glassware when you clean up!