You can do the reaction at zero degree and see if you get single spot. Else, you can use EDC/HOBt /DIPEA or HATU/DIPEA. I think its better to use DMF as solvent for this coupling reaction. Please see the attach paper as reference. Good luck

I agree you can do the reaction at zero degree but I also try to use Anhydrous DCM and put the reaction under dry nitrogene or argon atmosphere. Maybe you can dropwise a EDC solution in DCM over the DMAP/carboxylic acid/amine mixture.

Change the addition order, have DMAP, Acid and Amine stirring in DCM then add the EDC dropwise.

The major side products for diimide coupling reagents in the absence of an amine are acyl transfer to form the N-acylurea, and formation of the symmetric anhydride. Together with the desired O-acylisourea intermediate this could account for your three spots (assuming none of those are starting material or the urea side product).

Addition of HOBt will suppress acyl transfer.

You can use DMF instead of DCM and first you add acid in DMF at O degree Temp, after 10 min add amine.

What I did with the similar reaction is : add carboxylic acid and amine (or alcohol) in dry DCM with catalystic amount (5-10%) of DMAP and keep the mixture at zero degree. Then you add EDCI (as solid or in DCM solution) into your mixture, allow to increase the temperature to rt gradually. Usually reaction is complete in overnight.

Generally speaking you can reduce T to 0ºC (maybe increasing reaction time), making an inert atm with N2 or Ar. For the reaction conditions, first of all change your solvent to DMF (better for most cases if it is in good conditions) and change the order of your reagents: acid with DMF at 0ºC, then (HOBT), 10min later amine, 10min later base (DIPEA. TEA, DMAP) and finally 15 min later EDC (or DCC).

Using DCC you need to remove urea from crude by cold filtration a several acid and base washes.

Good luck

I have used a combination of EDCI, HOBt , DIPEA in DMF at Zero oC to RT. The procedure I followed is :

Take the carboxylic acid, EDCI, HOBt and amine. After Vac-refilling (Argon/vacuum alternatively) three times, add DMF. Cool to O oC. Add DIPEA dropwise, under argon. Slowly allow reaction to warm to RT. Monitor by TLC. 

As Few Contributors above said, DMF is better than DCM in the case of coupling reactions. HOBt is helpful. Make sure DIPEA is fresh and dry. 

Alternatively, I have found a following procedure using DCM and DMF.

From Journal of Medicinal Chemistry, 48(10), 3621-3629; 2005

General/Typical Procedure: 5-(3-Chlorophenylcarbamoyl)pentanoic Acid Pentyl Ester. To a solution of adipic acid (0.5 g, 3.42 mmol) and DMAP (0.42 g, 3.42 mmol) in dichloromethane (30 mL) and DMF (3 mL) was added 3-chloroaniline (0.44 g, 3.42 mmol) at room temperature. After stirring 10 min, 1-[3-(dimethylamino)-propyl]-3-ethylcarbodiimide hydrochloride (0.65 g, 3.42 mmol; EDCI) was added portionwise to the mixture at room temperature.The reaction was stirred for 12 h. A 1 N aqueous HCl solution (20 mL) was poured into the reaction mixture, and 5-(3-chlorophenylcarbomoyl)pentanoic acid was extracted with dichloromethane (30 mL). The organic solution was washed with water (50 mL), dried over Na2SO4, and concentrated. This residue was used for the next reaction without further purification.To the solution of the above carbamoylpentanoic acid (0.72 g, 2.80 mmol) in DMF (15 mL) was added K2CO3 (0.58 g, 4.21mmol) and 1-bromopentane (0.64 g, 4.21 mmol) at room temperature. After stirring for 12 h, the product was extracted with ether (30 mL), and the ether solution was washed with an aqueous solution of 1 N NaOH (15 mL) and water (40 mL), dried over Na2SO4, and concentrated. The residue was purified using silica gel column chromatography (hexane:ethyl acetate) 5:1). 2-cyclohexyl-N-phenylacetamide.

Check this thread too. 

https://www.researchgate.net/post/What_is_the_best_coupling_agent_HBTU_COMU_HATU_PyBOP_for_peptide_bond_formation

@ Hajeeth T. Try protecting the carboxylic group by phthalating it.

I use 1eq acid, 1.1eq amine, 0.2eq DMAP in DCM. Then drop-wise addition of EDC-HCl in DCM and stir overnight at ambient temperatures, argon atmos. Aqueous workup removes EDC byproduct. column chromatography to purify.

I have found that coupling alcohols to acids via EDC is a bit trickier because you can form molecular sink rearrangements of the activated EDC-intermediate complex that cannot be further displaced. 

For the coupling reaction of EDC/DMAP in DCM can you give the mechanism?

Hi @Goutham see the following papers

Synthesis:

Espinoza-Moraga, M.; Singh, K.; Njoroge, M.; Kaur, G.; Okombo, J.; De Kock, C.; Smith, P. J.; Wittlin, S.; Chibale, K. Bioorg. Med. Chem. Lett. 2016, 27, 658–661.

Kaur, G.; Singh, K.; Pavadai, E.; Njoroge, M.; Espinoza-Moraga, M.; De Kock, C.; Smith, P. J.; Wittlin, S.; Chibale, K. Med. Chem. Commun. 2015, 6, 2023–2028.

Reaction mechanism:

Montalbetti, C. A. G. N.; Falque, V. Tetrahedron 2005, 61, 10827–10852.

Tsakos, M.; Schaffert, E. S.; Clement, L. L.; Villadsen, N. L.; Poulsen, T. B. Nat. Prod. Rep. 2015, 605–632.

Here is the mechanism

Take acid(1eq), amine(1eq), EDC.Hcl (1.1eq)& HOBT(1.1eq) in DMF , at 0oC add DIEA(0.6eq) and stir at rt. add cool water and filter it to get solid(if ppt comes) otherwise extract with EtOAc n purify by column to remove HOBT. sure u ll get amide in high yeilds with HOBT as by-product. edc urea goes with water.

Can this acid amine coupling strategy will work same for acid and alcohol couling?

Pooja Joshi Yes, it will work. It's called Steglich reaction (named reaction)

Mohan Tirumalasetty how is it possible for edc urea to go with water as organic molecule, organic molecules in most cases doesn't go or dissolve in water in extraction except for salts, yes I understand if it's polar it can dissolve in water as polar solvent but I think that's not common in organic synthesis.

can somebody suggest a paper to find EDC/ DCC reaction procedure and mechanism.

You can change the sequence of addition. you can try reaction in THF. add acid and amine first then add DCC (in THF dilution)at RT, check the conversion. hope this will solve your problem.

hi, there , i work with amide synthesis, its better to run the reaction using acetonitirile if its not affecting your starting material, use cat hobt with EDC/dmap, add 2 eq DIPEA. the reaction goes smoothly after 24 hour or with TLC monitoring you can get your product with simple work up.