1) Reductive amination should be an alternative to the Boc-protection/alkylation/Boc cleavage sequence depending on what your R1 group is. For example if R1 = benzyl

CH2(CH2-NH2)2 + 2 PhCHO + NaCNBH3---> CH2(CH2-NHBenzyl)2

It should not be difficult to find published conditions which use reducing agents such as NaBH4, NaBH4 in acetic acid (check reviews by G. Gribble), and catalytic hydrogenaiton.

2) I suspect that your second step - alkylation of the bis-Boc derivative - may be your most difficult step. Solvents such as DMF and DMSO are likely required to make RBocNH alkylations to completion. Alkylation of sulfonamides goes smoothly (can be done in acetonitrile) but more aggressive conditions are needed to remove the sulfonyl blocking group. Look in the literature for condiitons to cleave aryl sulfonamides and if something promising [eg. Na/NH3(liq)] is available, your sequence could go as follows:

CH2(CH2-NH2)2 + 2 TsCl + 2 eq Et3N ---> CH2(CH2-NHTs)2

CH2(CH2-NHTs)2 + 2 R1Br + K2CO3 (CH3CN)---> CH2(CH2-NR1Ts)2

CH2(CH2-NR1Ts)2 ? Na/NH3(liq) or ? ---> CH2(CH2-NHR1)2

CH2(CH2-NHR1)2 + 2 CH2=CHCON(R2R3) --->

CH2(CH2-NHR1CH2CH2CON(R2R3)2

Best of luck!

Korban Oosthuizen Why don’t you start with diamine and acrylamides, then functionalizing the secondary amine using R-Br ?

Mo Aljuaid's suggestion ignores the problems of multiple and incomplete acrylamide reaction at amine N:

CH2(CH2-NH2)2 + 2 CH2=CHCON(R2R3) --->

CH2[CH2-NHCH2CH2CON(R2R3)]2 (desired)

+ CH2(CH2-NHCH2CH2CON(R2R3)CH2NH2 (incomplete)

+ CH2{CH2-N[CH2CH2CON(R2R3)]2}CH2NH2 (excess reaction at one N)

+ CH2{CH2-N[CH2CH2CON(R2R3)]2}2 (excess reaction at both Ns)

By the way, there was an error in the final structure of my second sequence - this product should not contain NH, rather

CH2(CH2-NHR1)2 + 2 CH2=CHCON(R2R3) --->

CH2{CH2-NR1CH2CH2CON(R2R3)}2

Your first reaction scheme is not complete as there is one additional disubstituted product that could be generated, the N,N-bis Boc derivative, on reaction with two equivalents of Boc anhydride. And what is the Boc anhydride byproduct? Trying to do prepare the 1,3-bis Boc derivative directly, as you propose, often leads to unexpected difficulties. A clean and efficient synthesis of a compound is often not the most direct route. I would suggest building your final product sequentially looking at 3-aminopropanol or N-(3-aminopropyl)phthalimide as possible starting materials. Preparation of the acrylamide as shown is more straight forward but using an excess of the amine as an HCL scavenger rather than tertiary amine (eg triethylamine) could result in addition across the double bond. Is the dialkylamine cyclic? There should be procedures for preparation of both an N,N'-bisalkyl diamine and an acrylamide in Org. Syn.

To JM Hinckley - I have an extremely hard time believing that -N(Boc)2 formation is a serious issue - carbamates are massively less reactive than monoalkylamines, and Boc protection is almost always run with moderate excess Boc reagent at room temperature or below. Can you cite anything that supports your claim that "Trying to do prepare the 1,3-bis Boc derivative directly, as you propose, often leads to unexpected difficulties"?

As far as stepwise construction of the two sides of the product using aminopropanol derivatives, this is of interest when different groups are wanted in the R1 position, but Korban hasn't asked for that and I see no stategic advantage when making symmetric products.

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Finally, If you are so certain that there are Org Synth procedures for making such products, why not provide a reference? Those of us answer questions such as these shouldn't be doing the questioners' literature searches for them, but if we point toward specific results we ought to be able to give clear leads in the form of authors, date ranges, research targets*, or other details that could allow questioners to locate literature precedents more quickly.

*There has been a lot of work on similar compounds in a wide range of journals over the past ~ 40 years, mostly as crown chelators or polyamines which are physiologically important as DNA counterions.

To J Kilgore. I spent over 40 years in the drug discovery business before retiring, much of this time developing usable synthetic routes to compounds that were previously accessable only with difficulty. For example, the preparation of 2,5,6-richlorobenzimidazole on the kilogram scale (JM Hinkley, AR Pocari, JA Walker II, EE Swayze and LB Townsend Syn Comm (1998)28 (9) 1703-1712) a key intermediate for the preparation of TCRB. The reported preparation of 2-chlorobenzimidazole by Harrison et al (JCS (1963) 2930-1937) is essentially useless for the preparation of this compound in any quantity. I did give you references. I, also, was not going to do any literature research for this person, who did not state the purpose of this synthesis, and reference to Org Syn should be sufficient to follow the suggestion, especially since OS procedures are readily available online. Assuming that this person is quite capable I should not have to provide more information. Finally, I am a bit perturbed by people who do not give a complete reaction scheme including "low percentage possibilities" for their proposed synthesis. (and yes I have isolated adenosine nucleoside derivatives where the 4- amino group was, unexpectedly, doubly BOCed). One must consider all possible products for a given reaction and use the Holmsian solution to eliminate those that do not fit the data, as things can be missed. In thinking outside the box, sometimes one finds the unexpected. By the way, in regards to accuracy, I do not have a "c" in the spelling of my last name thus I am not related to the infamous John Hinckley.

For the formation of diamine the first method may be some what better and can lead to product but during alkylation with RBr base like NaH or BuLi may be necessary.

The second method may fail. Alpha, beta amides are not good Michal acceptor hence attempt of Michael addition of amine to alpha, beta unsaturated amide may fail or can give very poor yield. Another problem is very natural tendency of polymerization of acryloyl chloride and acrylic acids....it can lead poor yield with impurities.

As an alternate method peptide coupling reagents like DCC (or DCCD) (dicyclohexyl carbodiimide), CDI (Carbo diimidazlole) can be used.

One equivalent of diamine, 2 equivalents of mono carboxylic acid can be coupled in presence of 2 equivalent. of DCC or one equivalent. of CDI on anhydrous THF or DCM solvent at r.t or lower temperature can furnish the desired diamide. It can then be reduced to diamine derivatives with suitable reducing agents like LAH etc.

If One uses a dicarboxylic acid as source of amide carbonyl then one equivalent of dicarboxylic acid 2 equivalents of amine should be allowed to react with 2 equivalent of DCC or 1 equivalent of CDI. Plenty of procedures are available in organic synthesis (collective volumes), proper journals or references may be available in Organic Chemistry portal. Please see Mitsonobu reactions , Peptide Coupling reagents etc. , Application of reagents like DCC, CDI, DEAD etc. If One uses ROH instead of RNH2 esters can also be prepared.

The method is very good and high yielding too.

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