S341 Research Proposal
As one of the major assignments for the course, you will write a synthesis proposal outlining
your plan to synthesize a novel derivative of 1,4-benzodiazepine, a common structure in
medically active compounds. This assignment is challenging for introductory organic students,
but one that you are capable of completing with an investment of time and effort. Along the
way, you will be amazed by how much you learn!
Background:
It is the goal of many medicinal chemists to design and synthesize compounds that have the
possibility of having therapeutic value. Chemists don’t just randomly start making “stuff,”
though; they have a rational plan. One such plan is to make derivatives or structural mimics of
compounds that are known to be biologically active. For instance, Valium is one compound in a
family of compounds that contains the 1,4-benzodiazepine structural motif. It turns out that there
are a number of other compounds with the same core structure that have a variety of medicinal
purposes. Therefore, it is logical that compounds that contain similar structures would have a
greater likelihood of being of value than a randomly generated compound.
Figure 1: Diazepam (Valium ®)
O
N
N
Cl
This is where the idea of structural mimics comes in. Molecules that are 1,5-benzodiazepines
have structural similarity to known drugs, and they are relatively straightforward to make, as
seen in Figure 2.
Figure 2: A synthesis of 1,5-benzodiazepine
NH2
acetone
H
N
catalyst
NH2
N
In this assignment, you will review the background literature to find out what is already known
about the 1,4-benzodiazepine and 1,5-benzodiazepine families: their activity, properties, and
synthesis. You will then propose your own target molecule that has not been reported in the
literature and give a rationale for why you chose it. Finally, you will write a formal proposal
with the background information, a proposed synthesis, safety and budget information.
Educational Goals: In this assignment, students will demonstrate the ability to
 locate primary and secondary literature sources
 read and summarize primary literature
 synthesize concepts from primary literature into a discussion
 design a synthesis for a target compound
 write a proposed synthesis of the target compound based on primary literature
Important Dates:
 July 6: Proposal Worksheet due
 August 2: Research Proposal Due
Formal Report Requirements:
Section 1: Literature Review
 Use at least one review article and secondary literature (such as the Merck Index) to
review Valium and any other medically used 1,4-benzodiazepines
 Discuss the “privileged structure” of 1,4-benzodiazepines, with reference to J. Med.
Chem. 1988, 31, 2235-2246.
 Include at least one (preferably more) primary references to structural analogs of 1,4benzodiazepines (including but not limited to 1,5-benzodiazapines)
 Refer to Heterocycles 2007, 71, 453-458, to draw a figure of the mechanism of formation
of 1,5-benzodiazapines from 1,2-diaminobenzene and a ketone. You should use their
mechanism as a guide, and fill in with all intermediates and arrows.
 Include at least one additional primary literature reference to a synthetic method for 1,5benzodiazepines
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Section 2: Proposal
Figure with a retrosynthesis of your approved target
Written procedures for your proposed synthesis based on primary literature reference
A paragraph of safety concerns, based on information from MSDS sheets. (Attach one
MSDS sheet to the back of your report.)
A chemical budget for ALL necessary chemicals (in appropriate amounts) based on the
online Aldrich catalog