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INTERCHAPTER
Medicinal Chemistry - Problems in Organic Synthesis
The synthesis of most of the drugs in this problem set can be found in one or the other of the
following references.
The Organic Chemistry of Drug Synthesis, Vol. 1-6, by D. Lednicer et al., John Wiley & Sons, Inc.
1980 - 1999.
Pharmaceutical Chemistry, Volume 1, drug synthesis, by H. J. Roth and A. Kleemann, Ellis
Horwood Series in Pharmaceutical Technology, Halsted Press, 1988.

MC.1 Following is an outline for this synthesis of diazepam.

H
N

O
CH3

Cl
4-Chloro-Nmethylaniline

NaOH, H2 O
(3)

Ac2 O
(1)

O
PhCCl, AlCl3
(2)

CH3

Cl

CH3
N
H
O

Cl

Cl
(4)

Cl

(B)

N
Cl

CH3
O

CH3
O
N

O
Cl

NH3
(5)

Cl

(A)
CH3
O
N

CH3
O
N
Cl

NH2
(6)

Cl
Diazepam

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Step 1: The amine nitrogen is first protected by treatment with acetic anhydride (Section 18.7B).
Whereas a 2 amine is a good nucleophile and will react with benzoyl chloride to give an
amide (Section 18.7A), the nucleophilicity of an amide nitrogen is so reduced that it will no
longer react with an acid chloride.
Step 2: Friedel-Crafts acylation (Section 21.1C) is directed by the amide nitrogen, which is
activating and ortho, para directing (Section 21.2A). Chlorine is also ortho, para directing but it
is deactivating and, therefore, the amide nitrogen takes precedence in directing the position of
further electrophilic aromatic substitution.
Step 3: The acetyl protecting group is removed by treatment with aqueous NaOH (Section 18.5D)
to give (B).
Step 4: Treatment of the amino group of (B) with chloroacetyl chloride results in acetylation
(Section 18.7A) to form the amide group of (A).
Step 5: Treatment of (A) with ammonia results in nucleophilic displacement of chlorine by an SN2
reaction (Section 8.3) to form a primary amine.
Step 6: Intramolecular reaction of the ketone and 1 amine of (A) results in formation of an imine
(a Schiff base, Section 16.10A) and completes this synthesis of diazepam.

MC.2 Following is an outline of this synthesis of lorazepam.

NH2

Et OOC

Cl

Cl

COOEt
H2N
Cl
(1)

H
N
Br2
(2)

Cl
(B)

C O

N
Cl

CH3 OH
Cl
(3)

Cl

Cl

(A)

O
COOEt
N OCH3
Cl

(C)

O
COOEt

COOEt

H
N

O
COOEt
N Br

Cl

NH2

H
N

OEt

hydrolysis and
decarboxylation
of the -ketoacid
(4)

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H
N

(D)

H
N

O
N

Cl

-3-

OCH3
Cl

BBr 3
(5)

O
OH
N

Cl

Cl
Lorazepam

Step 1: This step is divided into two parts. In the first part, reaction of the 1 amino group of
diethyl 2-aminopropanedioate with the carbonyl group of the diaryl ketone gives an imine (a
Schiff base, Section 16.10A). In the second part of this step, reaction between the 1aromatic
amine and an ester group gives an amide by nucleophilic acyl substitution (Section 18.7C).
Step 2: Bromination of this -ketoester proceeds by way of keto-enol tautomerism (Section 16.11)
followed by reaction of the enol with bromine (Section 16.12C).
Step 3: Solvolysis of the tertiary bromide proceeds by an SN1 mechanism (Section 8.3).
Step 4: Hydrolysis of the ester to a carboxylic acid (Section 18.5C) followed by heating results in
decarboxylation of the -ketoacid (Sections 17.9A and 19.3D).
Step 5: Boron tribromide, BBr3, is widely used to cleave ethers under very mild conditions. This
reagent is a colorless liquid most commonly supplied as a 1.0 M solution in CH2Cl2 or hexane.
It is highly sensitive to moisture and reacts rapidly with water to give B(OH)3 and HBr.
Cleavage of an ether requires one mole of BBr3 per mole of ether.

RCH2 OCH3 + BBr 3

RCH2 OBBr 2 + 3 H2 O

RCH2 OBBr 2 + CH3 Br

RCH2 OH + B(OH) 3
Boric acid

The first step in this ether cleavage reaction is an acid-base reaction between boron tribromide (a
Lewis acid) and the ether (a Lewis base) followed by loss of bromide ion. Bromide ion then
participates in an SN2 reaction, attacking the methyl carbon and displacing oxygen to give an
alkylborate ester. Hydrolysis of this ester gives the alcohol.

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RCH2 -O-CH3

-4-

Br
+ B Br
Br

Br
B Br

Br

Lewis acidbase reaction

RCH2 -O

Br
B
+ :Br
RCH2 -O
CH3

loss of
bromide ion

CH3

Br

SN 2

RCH2 -O-B

Br
Br

+ CH3 Br

MC.3 The synthesis of clonazepam is very similar to that of diazepam (MC.1) and lorazepam (MC.2).

HO

Cl

O
Cl

O
Cl

SOCl2

O
NHCCH3 NaOH

(1)
AlCl3
(3)

2-Chlorobenzoic
acid
NH2

Ac2 O
(2)

O2N

O
NHCCH3

O2N

(4)
Cl

O2N

p-Nitroaniline

NH2
O2N

O
Cl

Cl

O Cl

O2N

(5)

NH3
(6)

Cl

Cl

H
N
O2N

O
N

O
O NH2
Cl

HN
(7)

Clonazepam

N
O2N

Cl

Step 1: 2-Chlorobenzoic acid is treated with thionyl chloride to give an acid chloride (Section 17.8).

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Step 2: p-Nitroaniline is treated with acetic anhydride to form an amide (Section 18.7B), thus
protecting the amino group.
Step 3: Friedel-Crafts acylation (Section 21.1C) gives a diaryl ketone.
Step 4: Removal of the amine protecting by hydrolysis of the amide in aqueous base (Section
18.5D) gives the free amine. which is then treated in
Step 5: Treatment of the amine with chloroacetyl chloride (Section 18.7A) gives an -chloroamide.
Step 6: Nucleophilic displacement of the primary chloride by ammonia (Section 8.3) gives a
primary amine.
Step 7: Reaction of the primary amine with the nearby ketone gives an imine (Section 16.10A) and
closes the seven-membered ring of clonazepam.

MC.4 The synthesis of gabapentin involves two carbon-carbon bond forming steps. The first involves
condensation of an enolate anion (Section 19.2A) and ketone. The second involves a Michael
addition (Section 19.8A).

COOEt
O+
Cyclohexanone

COOEt

NaCN
(5)

COOEt

COOEt
(1)

COOEt

Tetrahedral
carbonyl addition
intermediate

Diethyl
malonate

(i) NaOH/ H2O

(ii) HCl/ H2 O
(2)

OH COOEt

NaOEt
(1)

COOH
COOH

CN
COOEt

heat
(3)

Pt / C
(6)

Et OH, H+
(4)
COOH

NH2
COOEt

ester
hydrolysis
(7)

COOEt

NH2
COOH
Gabapentin

Step 1: When treated with sodium ethoxide, diethyl malonate is converted to its enolate anion
(Section 19.7) and then, in a carbonyl condensation related to the aldol reaction (Section 19.2)
and the Claisen condensation (Section 19.3), adds to the carbonyl carbon of cyclohexanone to

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give a tetrahedral carbonyl addition compound. Dehydration of this addition compound gives
an ,-unsaturated diester.
Step 2: Base-promoted hydrolysis of the diester in aqueous base followed by acidification with
HCl (Sections 18.5C and 19.7) gives an ,-unsaturated dicarboxylic acid.
Step 3: Heating the -dicarboxylic acid results in decarboxylation (Section 17.9B) and gives an ,unsaturated carboxylic acid.
Step 4: Treatment of the carboxylic acid with ethanol in the presence of a p-toluenesulfonic acid
catalyst (Fischer esterification, Section 17.7A) converts the carboxyl group to an ethyl ester.
Step 5: Michael addition (Section 19.8A) of cyanide ion to the ,-unsaturated ester gives a cyanoester.
Step 6: Treatment of the cyano group with hydrogen over a platinum-on-charcoal catalyst reduces
the cyano group to a primary amine.
Step 7: Hydrolysis of the ester group (Section 18.5C) using either aqueous NaOH or HCl gives
gabapentin.

Note that although gabapentin is shown in the problem as containing primary amino and
carboxyl groups, it is better represented as an internal salt resulting from proton transfer from the
acidic carboxyl group to the basic amino group.
intramolecular
acid/base reaction

NH2

NH3 +

COOH
Gabapentin

COO-

MC.5 Following is the outline for this synthesis of phensuximide.

CHO
Benzaldehyde

CN
COOEt
Ethyl
cyanoacetate

NaOEt

CN
H

COOEt
(A)

KCN

CN
COOEt

NC
(B)

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Et OH, H+

1 . NaOH, H2 O
2 . HCl, H2 O
3. heat

-7-

HOOC
(C)

COOH

CH3 NH2
Et OOC
(D)

COOEt

O
N
CH3
Phensuximide
O

(a) As shown in the following table, a cyano group has about the same acid-strengthening effect
on an -hydrogen as does an ester group. Thus, the acidity of an -hydrogen of ethyl
cyanoacetate is comparable to that of an -hydrogen in diethyl malonate (pKa 13, Section 19.7).

pK a
O
RCH2 COEt
RCH2 C N

pK a

24-25

O
O
Et OCCH2 COEt

13

25

N CCH2 C N

11

When treated with sodium ethoxide, ethyl cyanoacetate is converted to its enolate anion
(Section 19.7) and then, in a carbonyl condensation related to the aldol reaction (Section 19.2)
and the Claisen condensation (Section 19.3), adds to the carbonyl carbon of benzaldehyde to
give a tetrahedral carbonyl addition compound. Dehydration of this addition compound gives
an ,-unsaturated cyanoester.
(b) Treatment of (A) with KCN results in Michael addition (Section 19.8A) of cyanide ion to the carbon of the ,-unsaturated cyanoester.
(c) Treatment of (B) with NaOH, H2O results in base-promoted hydrolysis of the ester and cyano
groups (Sections 18.5C and 18.5E)) to carboxylic salts. Acidification with HCl and heating
results in decarboxylation of the -dicarboxylic acid (Section 17.9B).
(d) Treatment of the dicarboxylic acid with ethanol in the presence of an acid catalyst such as ptoluenesulfonic acid (Fischer esterification, Section 17.7A) converts each carboxyl group to an
ethyl ester.

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(e) Treatment of the diester with methylamine results in conversion of one ester and then the
other to an amide (Section 18.7C). Each reaction is an example of nucleophilic acyl substitution
(Section 18.4).

In an even more direct route to phensuximide, phenylsuccinic acid is treated with methylamine to
give an ammonium salt and then heated to form the imide.

CH3 NH2 , heat

COOH

HOOC

O
N
CH3
Phensuximide
O

+ H2 O

(f) For the synthesis of methsuximide, use acetophenone as the starting carbonyl compound. For
the synthesis of ethosuximide, use 2-butanone as the starting material and ammonia as the
amine to form the five-membered imide ring.

CN

same steps as for

phensuximide
O

COOEt
O
Acetophenone

+
O
2-Butanone

CN
COOEt

Ethyl
cyanoacetate

Ethyl cyanoacetate

O
N
CH3
Methsuximide

same steps as for

phensuximide

NH3
Et OOC

COOEt

N
H

Ethosuximide

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(g) Only ethosuximide has a hydrogen on the imide nitrogen. It is the most acidic and has an acidity
comparable to that of succinimide (pKa 11, Section 18.2). The imide anion is stabilized by
resonance interaction with the carbonyl groups on either side of it.

MC.6 The synthesis of diethylcarbamazine can be accomplished in five steps. Key to forming each
new C-N bond is the nucleophilicity of nitrogen.

CH3 NH2 +
Methylamine

Ethylene
oxide

OH

(1)

O
Cl

Cl

OH

O
OEt

(4)

SOCl2
(2)

OEt

Cl
N

NH3
(3)

N
N-Methylpiperazine

O
N

(5)

N
Diethylcarbamazine

Step 1: Treatment of methylamine with two moles of ethylene oxide results in nucleophilic
opening of the highly strained epoxide ring (Section 11.9B).
Step 2: Treatment of the diol with two moles of thionyl chloride (Section 9.5C) gives a dichloride.
Step 3: Treatment of the dichloride with one mole of ammonia results in nucleophilic
displacement of first one chloride and then the second to form a six-membered nitrogencontaining ring. Note that the dichloride has the structural characteristics of a nitrogen
mustard (Section 8.5) and displacement of chlorine most probably involves neighboring group
participation by the tertiary amine of the mustard.
Step 4: Nucleophilic displacement of chlorine from ethyl chloroformate by nitrogen (Section
18.7A) gives the carbamic ester; that is, a derivative of carbonic acid that is both an amide and
an ester. Note that, in the reaction of the amine with ethyl chloroformate, it is -Cl that is
displaced and not the -OEt group; chloride is a more stable anion than ethoxide ion and,
therefore, is more readily displaced from ethyl chloroformate than ethoxide ion.

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Step 5: Treatment of the carbamide with diethylamine (Section 18.7C) gives diethylcarbamazine
by nucleophilic acyl substitution.

In an alternative synthesis, N-methylpiperazine is treated with phosgene, the diacid chloride of

carbonic acid, to give a carbamoyl chloride. This acid chloride is then treated with diethylamine to
give diethylcarbamazine.

O
N

H Cl

O
OEt

(4')

N
N

Cl

(5')

N- Methylpiperazine

Diethylcarbamazine

MC.7 Following is an outline for this synthesis of amitriptyline.

1.

2. H3 O+
(2)

H3 PO4
(1)
COOH

O
(B)

(A)

HO

Cl, Mg

(CH3 ) 2 NH
(4)

HBr
(3)

Br

(C)

(D)

Amitriptyline

Step 1: This step is a type of electrophilic aromatic substitution resulting in acylation of the
aromatic ring. The electrophile is an acyl cation.

+ H-O-PO3 H2
:

C OH
O

+
C O H
O
H

+ -:O-PO3 H2

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+
+ H-O-PO3 H2
C+
O
An acyl cation

-:

O-PO3 H2

Step 3: This transformation is initiated by proton transfer to the -OH group of the 3 alcohol to
give an oxonium ion followed by loss of H2O to give a tertiary carbocation. What must be done
next is opening of the highly-strained three-membered ring and formation of a primary
bromide. Because it is not acceptable to propose a primary carbocation, propose that opening
of the three-membered ring and formation of the primary bromide are concerted
(simultaneous).

H O
+
H

HO

Br-H

+
:Br

Br

In an alternative synthesis of amitriptyline, the ketone (B) is treated with the Grignard reagent
formed from 3-dimethylaminopropyl bromide to give a tertiary alcohol. Acid-catalyzed
dehydration of the alcohol gives amitriptyline.
BrMg

N
HCl

O
(B)

(2')

HO
N

MC.8 Following is an outline for this given synthesis of fluoxetine.

(3')

N
Amitriptyline

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O
H

-12-

HO

(B)

(A)

(C)

(D)

OH
O

F3 C
CH3 ONa

SOCl2

NaBH4

(1)

Cl

O
Cl

OEt

F3 C

OEt
C
N

F3 C
(E)

1 . NaOH, H2 O

2 . HCl, H2 O

(F)
COOH
N

H
N

F3 C

F3 C
An N-substituted
carbamic acid

Fluoxetine

(a) Conversion of (A) to (B) involves a Michael addition (Section 19.8A) of dimethylamine to the
,-unsaturated ketone.
(b) Conversion of (B) to (C) is a two-electron reduction of the carbonyl group of the ketone to a
primary alcohol. Suitable reducing agents are H2 in the presence of a transition metal catalyst
such as Pt or Pd (Section 16.14A), or a metal hydride reduction using NaBH4 (Section 16.14B).
(c) To convert (C) to (D) treat the secondary alcohol group with thionyl chloride, SOCl2 (Section
9.5C).
(d) The first step in the conversion of (E) to (F) is nucleophilic addition of the tertiary amine
nitrogen to the carbonyl group of ethyl chloroformate to give a tetrahedral carbonyl addition
intermediate (TCAI) followed by its collapse to give a quaternary amide with a positive charge
on the nitrogen of the amide. Nucleophilic attack of chloride (an SN2 reaction, Section 8.3) on
one of the two methyl group and displacement of nitrogen gives the ethyl carbamide and
chloromethane.

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CH3
O
+
N
OEt
CH3 Cl

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Cl

-13-

O: -

R +N

OEt
C
CH3
R +N
CH3
O

OEt
CH3
CH3

A TCAI

O
R

:Cl-

OEt
C
N

CH3

+ CH3 Cl

(f) (F) is converted to fluoxetine by base-promoted hydrolysis of the ester (Section 18.5C) using
aqueous NaOH to give the N-substituted carbamic acid followed by its decarboxylation.

An alternative synthesis of fluoxetine begins with nucleophilic aromatic substitution (Section 21.3)
of the fluorine atom of 4-trifluoromethylfluorobenzene. Removal of the phthalimide protecting
group by hydrazinolysis followed by alkylation of the amino group gives fluoxetine.
O
Na+ -O

O
N

O
(1)

F3 C

F3 C

4-Trifluoromethylfluorobenzene

O
N2H4
(2)

F3 C

NH2

O
Cl

H
N

O
OEt

(3)

F3 C

O
LiAlH4
(4)

OEt

F3 C

H
N
Fluoxetine

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MC.9 Following is an outline for this synthesis of venlafaxine.

Cl

O
+
CH3 O
Anisole

Cl

Cl

AlCl3
(1)

Chloroacetyl
chloride

N
O

(2)

CH3 O

CH3 O

O
NaBH4
(3)

N
OH

CH3 O

SOCl2
(4)

Cl
CH3 O

Mg ,

OH

(5)
CH3 O
Venlafaxine

Step 1: Synthesis begins with a Friedel-Crafts acylation (Section 21.1C) of anisole.

Step 2: Nucleophilic displacement of the primary chloride by dimethylamine (SN2, Section 8.3)
gives the tertiary amine.
Step 3: Metal hydride reduction of the ketone (Section 16.14B) gives the secondary alcohol.
Catalytic reduction using H2 and a transition metal catalyst such as Pd or Pt (Section 16.14A)
may also be used to reduce the ketone.
Step 4: Treatment of the secondary alcohol with thionyl chloride (Section 9.5C) converts the
alcohol to a chloride.
Step 5: The final step in the synthesis is a Grignard reaction with cyclohexanone followed by
treatment of the magnesium alkoxide salt with aqueous acid (Section 16.6A).

MC.10 The synthesis of moclobemide can be carried out by the following scheme.

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N

O
Morpholine

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KN3

(1)
OH

N
O

N3

Ethylene
oxide

SOCl2

O
(4)

Cl

N
O

(2)

(5)

H2 / Pt

NH3

NH2

N
O

(3)

(7)
Cl
HO

SOCl2
(6)

Cl
N

Cl

O
O

Cl

N
O
Moclobemide

Step 1: Treatment of ethylene oxide with morpholine results in nucleophilic opening of the highly
strained three-membered ring (Section 11.9B) and formation of a primary alcohol.
Step 2: Treatment of the primary alcohol with thionyl chloride (Section 9.5C) converts the alcohol
to a chloride.
Steps 3, 4, and 5: The most direct way to convert the primary halide to a primary amine is
displacement of chloride by ammonia (SN2, Section 8.3). However, as pointed out in Section
22.8A, unless reaction conditions are very carefully controlled, there is formed a complex
mixture of primary, secondary, tertiary amines as well as a quaternary ammonium salt. An
alternative strategy is to use azide ion, N3-, as the nitrogen-containing nucleophile (Section
22.8B). The resulting alkyl azide is no longer a nucleophile. Reduction of the alkyl azide to the
desired primary amine is accomplished using H2/Pt.
Step 6: The carboxylic acid is converted to its acid chloride by reaction with thionyl chloride
(Section 17.8).
Step 7: The synthesis is completed by reaction of the acid chloride and amine (Section 18.7A) to
give the amide group of moclobemide.

An alternative synthesis of moclobemide begins with aziridine, the nitrogen analog of ethylene
oxide. Acylation of the amine nitrogen with 4-chlorobenzoyl chloride (Section 18.7A) gives an

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aziridine amide. Treatment of the aziridine ring with morpholine results in nucleophilic opening
of the ring to give moclobemide.

Cl

Cl
NH + Cl
Aziridine

N
O

H
N

N
O

Cl

O
Moclobemide

MC.11 Following are steps in this synthesis of nabumetone.

O
3
2

CH3 O

Cl

CH2 O, HCl
(1)
7

NaOEt ,
COOEt
(2)

CH3 O

2-Methoxynaphthalene

HCl, H2 O

NaOH, H2 O
CH3 O

COOEt

(3)

COO- Na+

CH3 O

(4)

O
COOH

CH3 O

O
heat
(5)

CH3 O

Nabumetone

(a) Chloromethylation is initiated by proton transfer to formaldehyde to give a resonancestabilized cation.

H

H
H

+H
O

H
+
H

H
O
:

O: + H-Cl

+ : Cl-

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This cation is sufficiently electrophilic to react with 2-methoxynaphthalene to give a

resonance-stabilized cation. Comparing contributing structures for attack and positions 6 and
7 of the aromatic ring, we see that if attack occurs at carbon 6, oxygen of the methoxyl group
can participate in stabilizing the cation. If attack occurs at carbon 7, oxygen of the methoxyl
can not participate in stabilizing the cation. Because cation 6 is more stable, there is a lower
energy of activation for its formation and it is the preferred cation intermediate.

H
6

CH2 OH

CH3 O
+

CH3 O
6

+
CH3 O

CH2 OH

+H
O

H
+
7

CH3 O

+
CH2 OH

CH3 O

CH2 OH

Proton transfer from cation 6 to chloride ion completes the electrophilic aromatic substitution
and gives the hydroxymethyl group.
H
6

CH2 OH

:Cl-

CH2 OH

CH3 O
+

CH3 O

Chloromethylation is completed by proton transfer to oxygen of the CH2OH group to give an

oxonium ion, loss of H2O to give a resonance-stabilized benzylic carbocation, and finally
reaction of the benzylic carbocation with chloride ion.

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+
CH2 -OH2

CH2 OH
+ H-Cl

CH3 O

CH3 O
CH2 +

CH2 Cl

:Cl-

CH3 O

CH3 O

(b) The steps in the acetoacetic ester synthesis (Section 19.6) are shown in the outline for the
synthesis.
(c) Following are structural formulas of 6-methoxynaphthylacetic acid, ibuprofen, and naproxen.

COOH

COOH

COOH

CH3 O
6-Methoxynaphthylacetic
acid

CH3 O
Naproxen

Ibuprofen

MC.12 Following is an outline of this synthesis of racemethorphan.

O
Cl
NC

O N

H2N
LiAlH4

H3 PO4

CH3 O

(1)

(3)

(2)

(A)

CH3 O

(B)

NaBH4
(4)
(D)

(C)

H
N

CH3 O

CH3 O

N
H3 PO4
(5)

(redraw)

(E)

CH3 O

(E)

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-19O

Et O

H3 C
N
H

Et O
Cl
(6)
CH3 O

(7)
CH3 O

(F)

LiAlH4

CH3 O

(G)

Racemethorphan

(a) Lithium aluminum hydride reduction of the nitrile gives a primary amine (Section 18.11C).
(b) The reagent is 4-methoxybenzoyl chloride. Reaction of this acid chloride with the primary
amine gives an amide (Section 18.7A).
(c) This intramolecular cyclization is initiated by protonation of the carbonyl group of the amide.
The resulting cation (a Lewis acid) reacts with the carbon-carbon double bond of the alkene (a
Lewis base) to give a carbocation intermediate, loss of a proton from which gives the carboncarbon double bond of the newly formed six-membered ring. Loss of H2O from the -amino
alcohol gives the imine (Schiff base). In this mechanism, phosphoric acid is represented by HA.

H
A-H

H
+ N
H O

:O N

H
HO N
+

H
CH3 O

CH3 O

(C)

:A -

CH3 O
H

HO N

N
-H2 O

CH3 O

CH3 O

(D)

(d) Conversion of (E) to (F) involves an electrophilic aromatic substitution like that described in
Section 21.1D. In this case, the attacking electrophile is the carbocation generated by
protonation of the carbon-carbon double bond of the substituted cyclohexene ring.

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H-A

H
+

CH3 O

(E)

CH3 O

N
H

CH3 O

(e) The reagent is ethyl chloroformate.

(f) The reagent is lithium aluminum hydride.

+ H
:A -

N
H

CH3 O

(F)