Question

Problem 2: Diazepam, marketed as Valium, belongs to the class of benzodiazepine anxiolytic medications (a diazepine is a compound with two nitrogens in a 7-membered ring system). Valium is one of the most commonly prescribed anti-anxiety medications that produce a calming effect. Write the curved-arrow mechanisms for all four steps in the synthesis of diazepam indicated below. Add extra sheets to paper to write the mechanisms in detail. Valium Diazepam STEP 1 STEP 2 NH₂ 0NH 0 ONHO lquid NH -33 °C, 5 hrs NaOH (1 eq.), 10 °C, 30 mins, with dioxane as solvent STEP 3 pyridine (solvent), heat at reflux with Dean-Stark Trap. 1 hour No STEP 4 1. NaOCH, in CH OH 2. CH I in DMF, 30 min Diazepam (Valium) NOTE the 7-membered ring!! sep 1

Answer 1

Solution: The qiun reaction is NH NH2 0 Naoh (1 e4 10c C1 CI 3umin diorane Step-4 Mechanism Step-1 N-H NH2 e Na oH Step- 1 Step- 2 cl CI Where R = + H2o t Nacl. acid chloride Nucleophile attack of- NH2 on tep-1 step-2 Reroval of hadrogen from quatarnay nitrogan to gik Mzo Nad by produdt NH2 N4 lia NH3 NH 330C shr C1

<sup>Mechanism: Step- 2 4 NH NH liq NH3 NH step-2 Step-1 Cl Nиz NH cl b SN pathuay Nudeo phille ccttack of NH3 step-1 step-2: Removal of proton frum quatornary nitragen b1 # NH2 Psridine reflux NH Mechanism step- 3 H N H N Step-i Step-2 1 2

H N CNy Step 3 И Step-4 ketone step- 1: Nudeophile attack ot NH2 O0 step-2 Then protonat on of o b1 step-3 Removal of bj lone pair ot nitragen otom. Step-: Removal of Proton N-H equillibrium toward praducd bPyridinge and shift cH3 1 NaucH3 in CH30H 2.met, DmF

Mechanism Step-4 эсu3 бсиз NaocHs DmF CH30H step-2 Step-1 CHз N. step 1: Removal of -NH Proton by Na ocH3 A anion generation Step-2 N-methylof ion in io CH3I DMF</sup>