Question

14. The following sequence of reactions outlines a synthesis for the calcium-channel blocker Diltiazem, which is used to treat high blood pressure and to control angina (chest pain). A 1. NaH, THE 1 OH CI pyridine 2. p-methoxy- benzaldehyde 4 ~ SH -NO2 H2 p-TsOH muy a BTSCH o Han Pd-C heat OCH COCH3 OCH Ac20 1. Nah E- -OH pyridine 2. F Diltiazem

Answer 1

ANSWER - Question 14a:

Reagents A:

• The conversion of 1 to 2 we must use an Grignard reagent::

Mg ОН 2) Hot

Reagents B:

• The transformation of 2 to 3 is the synthesis of an ester using a acid halide

Qurante. Lora OH Pyridine

Structure C:

The epoxyde in compound 5 is opened, and the reactant atacks the carbon with the phenyl substituent because this is the most electrophilic carbon

Structure D:

The catalytic hydrogenation of structure C reduces the NO₂ group to an NH₂ group

Structure E:

The group OH of compound 6 is transformed into an OAc group with the acetic anhydride

OCH Oy NO

Reagent F:

The NaH deprotonates the structure E, then, it attacks the reagent F to produces the compound 7

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ANSWER - Question 14c:

The proposed mechanism is:

NaH THF 0 H2 O + Na A OCH HACO -O: + Naci OCH3

• The NaH deprotonates the ester alpha-carbon of compound 3 to form an enolate.
• This enolate attacks the aldehyde-carbon of compound 4 (condensation reaction) to form an alcoxyde.
• Finallly, the negative oxygen attack the ester alpha-carbon by nucleophilic substitution to eliminates the Cl atom and form the epoxyde