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The Workhorse Reactions: Amides and Cross-Couplings

A handful of robust reactions account for most bonds made in discovery chemistry. Get comfortable with amide coupling, Suzuki and Buchwald–Hartwig couplings, and reductive amination — what they connect, what reagents to reach for, and how to keep them clean.

Why so few reactions do so much

Surveys of medicinal-chemistry literature keep finding the same result: a small set of reactions builds the majority of bonds. Amide coupling alone often tops the list, with Suzuki coupling, Buchwald–Hartwig amination, and reductive amination close behind. This is not laziness — these reactions are reliable, functional-group tolerant, and fed by huge catalogs of building blocks. Mastering them gives you most of practical synthesis.

The four you must know cold

  1. Amide coupling joins a carboxylic acid and an amine. Activate the acid with a coupling reagent (HATU, EDC/HOBt, or T3P) plus a base like DIPEA. It tolerates most groups and runs at room temperature.
  2. Suzuki coupling forms a C–C bond between an aryl halide and a boronic acid/ester, with a Pd catalyst and base. It is how most biaryls and aryl–heteroaryl links are made.
  3. Buchwald–Hartwig amination forms a C–N bond between an aryl halide and an amine, again Pd-catalyzed with a ligand and base. It installs anilines and N-aryl heterocycles cleanly.
  4. Reductive amination joins an aldehyde or ketone to an amine via an imine, reduced in situ by NaBH(OAc)₃ or NaBH₃CN. It is the fastest way to make secondary and tertiary amines.
Amide:     R-CO2H + H2N-R'  --[HATU, DIPEA, DMF]-->  R-CO-NH-R'
Suzuki:    Ar-Br + Ar'-B(OH)2 --[Pd(PPh3)4, K2CO3, dioxane/H2O]--> Ar-Ar'
Buchwald:  Ar-Br + H2N-R  --[Pd2(dba)3, XPhos, Cs2CO3, toluene]--> Ar-NH-R
Red.amin.: R-CHO + H2N-R' --[NaBH(OAc)3, AcOH, DCE]-->  R-CH2-NH-R'
Default conditions worth memorising as a starting point — then optimise per substrate.

Keeping couplings clean

Two themes recur. First, competing nucleophiles: a free amine or acid elsewhere in the molecule may interfere, which is when you reach for a protecting group. Second, chemoselectivity with two halides — bromides usually react faster than chlorides in Pd chemistry, letting you couple one site at a time. Plan the *order* of bond-forming steps so the most sensitive group is installed last.