Solution: Propose a mechanism for the following

Spermine is a naturally occurring compound that contributes to the characteristic odor of semen. Classify each nitrogen atom in spermine as primary, secondary, or tertiary. H2N N H N H NH2 Spermine

Clomipramine is marketed under the trade name Anafranil and is used in the treatment of obsessive compulsive disorder. Clomipramine N Cl N (a) Identify which nitrogen atom in clomipramine is more basic and justify your choice. (b) Draw the form of clomipramine that is expected to predominate at physiological pH.

Cinchocaine is a long-acting local anesthetic used in spinal anesthesia. Identify the most basic nitrogen atom in cinchocaine. Cinchocaine N O O N H N

For each pair of compounds, identify the stronger base. N N vs. (a) N N O (b) vs. HN H N HN NH (c) vs

Draw the structure of each of the following compounds: (a) N-Ethyl-N-isopropylaniline (b) N,N- Dimethylcyclopropylamine (c) (2R,3S)-3-(N,N-Dimethylamino)-2-pentanamine (d) Benzylamine

Consider the structure of lysergic acid diethylamide (LSD), a potent hallucinogen containing three nitrogen atoms. One of these three nitrogen atoms is significantly more basic than the other two. Identify the most basic nitrogen atom in LSD and explain your choice. LSD N H N O N H

Identify the number of chirality centers in each of the following structures: NH2 (a) N (b) (c) N

Assign a name for each of the following compounds: NH2 (a) O NH2 (b) N (c) NH2 (d) Br N (e) N (f)

Draw all constitutional isomers with molecular formula C4H11N and provide a name for each isomer.

Draw all tertiary amines with molecular formula C5H13N and provide a name for each isomer. Are any of these compounds chiral?

Each pair of compounds below will undergo an acid-base reaction. In each case, identify the acid, identify the base, draw curved arrows that show the transfer of a proton, and draw the products. N OH O (a) + N OH O (b) +

Draw the structure of the major product obtained when aniline is treated with each of the following reagents: (a) Excess Br2 (b) PhCH2COCl, py (c) Excess methyl iodide (d) NaNO2 and HCl followed by H3PO2 (e) NaNO2 and HCl followed by CuCN

Identify how you would make each of the following compounds from 1-hexanol: (a) Hexylamine (b) Heptylamine (c) Pentylamine

Identify how you would make hexylamine from each of the following compounds: (a) 1-Bromohexane (b) 1-Bromopentane (c) Hexanoic acid (d) 1-Cyanopentane

Tertiary amines with three different alkyl groups are chiral but cannot be resolved because pyramidal inversion causes racemization at room temperature. Nevertheless, chiral aziridines can be resolved and stored at room temperature. Aziridine is a three-membered heterocycle containing a nitrogen atom. The following is an example of a chiral aziridine. In this compound, the nitrogen atom is a chirality center. Suggest a reason why chiral aziridines do not undergo racemization at room temperature. N

Lidocaine is one of the most widely used local anesthetics. Draw the form of lidocaine that is expected to predominate at physiological pH. Lidocaine N O H N

Propose a mechanism for the following transformation: H H O NH3 CH3NH2 [H+] NaBH3CN

When aniline is treated with fuming sulfuric acid, an electrophilic aromatic substitution reaction takes place at the meta position instead of the para position, despite the fact that the amino group is an ortho-para director. Explain this curious result. NH2 NH2 SO3H Fuming H2SO4

para-Nitroaniline is an order of magnitude less basic than metanitroaniline. (a) Explain the observed difference in basicity. (b) Would you expect the basicity of ortho-nitroaniline to be closer in value to meta-nitroaniline or to para-nitroaniline?

Methadone is a powerful analgesic that is used to suppress withdrawal symptoms in the rehabilitation of heroin addicts. Identify the major product that is obtained when methadone is subjected to a Hofmann elimination. Methadone O N

In general, nitrogen atoms are more basic than oxygen atoms. However, when an amide is treated with a strong acid, such as sulfuric acid, it is the oxygen atom of the amide that is protonated, rather than the nitrogen atom. Explain this observation.

Propose a synthesis for each of the following transformations: N O (a) COOH (b)

Draw a mechanism for the last step of the Gabriel synthesis, performed under basic conditions. N O O R RNH2 COO COO NaOH @ @ +

One variation of the Gabriel synthesis employs hydrazine to free the amine in the final step of the synthesis. Draw the by-product obtained in this process. N O O R RNH2 H2N NH2 + ?

Predict the major product for each of the following reactions: N H 1) Excess MeI 2) Ag2O, H2O, heat (a) ? N O O H 1) KOH 2) EtBr 3) H2NNH2 (b) ? Br 1) NaCN, DMSO 3) SOCl2 4) excess NH3 2) H3O+, heat (c) ? 1) HNO3, H2SO4 2) Fe, H3O+ 3) NaNO2, HCl (d) 4) CuCN ?

Fill in the missing reagents: O N CHO CHO NH2 NH2 a b c d

In this chapter, we explained why pyrrole is such a weak base, but we did not discuss the acidity of pyrrole. In fact, pyrrole is 20 orders of magnitude more acidic than most simple amines. Draw the conjugate base of pyrrole and explain its relatively high acidity.

Rimantadine is an antiviral drug used to treat people infected with life-threatening influenza viruses. Identify the starting ketone that would be necessary in order to prepare rimantadine via a reductive amination. Rimantadine NH2

Benzphetamine is an appetite suppressant that is marketed under the trade name Didrex and used in the treatment of obesity. Identify at least two different ways to make benzphetamine via a reductive amination process. Benzphetamine N

Draw the product formed when each of the following compounds is treated with NaNO2 and HCl: NH2 (a) H N (b)

Consider the structure of the azo dye called alizarine yellow R (below). Show the reagents you would use to prepare this compound via an azo coupling process. N N OH OH O O2N

Draw the major product(s) that are expected when each of the following amines is treated with excess methyl iodide and then heated in the presence of aqueous silver oxide. NH2 (a) NH2 (b)

Predict the major product(s) for each of the following reactions: NO2 Br 1) Fe, H3O+ 2) NaOH (a) ? NH2 O [H+] (b) + NaBH3CN ? CN 1) xs LAH 2) H2O (c) ? N O 1) xs LAH 2) H2O (d) ?

meta-Bromoaniline was treated with NaNO2 and HCl to yield a diazonium salt. Draw the product obtained when that diazonium salt is treated with each of the following reagents: (a) H2O (b) HBF4 (c) CuCN (d) H3PO2 (e) CuBr

Draw the expected product of the following reductive amination: O NH2 [H2SO4] NaBH3CN ?

Starting with benzene and any reagents with three or fewer carbon atoms, show how you would prepare each of the following compounds: N H (a) Cl Cl Cl O NH2 (b) N H O (c) N N NH2 (d)

Draw the structures of all isomeric amines with molecular formula C6H15N that are not expected to produce any signal above 3000 cm-1 in their IR spectra.

When the following compound is treated with excess methyl iodide, a quaternary ammonium salt is obtained that bears only one positive charge. Draw the structure of the quaternary ammonium salt. O N H NH2

Draw a mechanism for the following transformation: N H O N H N Cl O N H Cl@ ! + +

A compound with molecular formula C5H13N exhibits three signals in its proton NMR spectrum and no signals above 3000 cm-1 in its IR spectrum. Draw two possible structures for this compound.

Coniine has molecular formula C8H17N and was present in the hemlock extract used to execute the Greek philosopher Socrates. Subjecting coniine to a Hofmann elimination produces (S)- N,Ndimethyloct-7-en-4-amine. Coniine exhibits one peak above 3000 cm-1 in its IR spectrum. Draw the structure of coniine.

Piperazine is an antihelminthic agent (a drug used in the treatment of intestinal worms) that has molecular formula C4H10N2. The proton NMR spectrum of piperazine exhibits two signals. When dissolved in D2O, one of these signals vanishes over time. Propose a structure for piperazine.

Primary or secondary amines will attack epoxides in a ringopening process: RNH2 OH NR H O For substituted epoxides, nucleophilic attack generally takes place at the less sterically hindered side of the epoxide. Using this type of reaction, show how you might prepare the following compound from benzene, ammonia, and any other reagents of your choice. N HO H

Phenacetin was widely used as an analgesic before it was removed from the market in 1983 on suspicion of being a carcinogen. It was widely replaced with acetaminophen (Tylenol), which is very similar in structure but is not carcinogenic. Starting with benzene and using any other reagents of your choice, outline a synthesis of phenacetin. Phenacetin N O H O

Propose a mechanism for the following process: O N2 CO2 O Heat N O O N @ ! + +

Draw the structure of the compound with molecular formula C6H15N that exhibits the following 1 H NMR and 13C NMR spectra: Proton NMR Carbon NMR 2 3 45.8 Chemical Shift (ppm) Chemical Shift (ppm) 3.0 2.8 2.6 2.22.4 2.0 1.8 1.6 1.4 1.2 1.0 0.8 0.6 0.4 70 60 50 40 30 20 10 0 11.3

Draw the structure of the compound with molecular formula C8H11N that exhibits the following 1 H NMR and 13C NMR spectra: Proton NMR Carbon NMR 5 138.8 128.4 126.1 43.5 40.0 128.8 2 2 2 Chemical Shift (ppm) Chemical Shift (ppm) 7 140 130 120 110 100 90 80 70 60 50 40 6 5 4 3 2 1

Using benzene as your only source of carbon atoms and ammonia as your only source of nitrogen atoms, propose an efficient synthesis for the following compound:

Propose an efficient synthesis for the following transformation: N

When 3-methyl-3-phenyl-1-butanamine is treated with sodium nitrite and HCl, a mixture of products is obtained. The following compound was found to be present in the reaction mixture. Account for its formation with a complete mechanism (make sure to show the mechanism of formation for a nitrosonium ion).

Guanidine lacks a negative charge but is an extremely powerful base. In fact, it is almost as strong a base as a hydroxide ion. Identify which nitrogen atom in guanidine is so basic and explain why guanidine is a much stronger base than most other amines. H2N NH2 NH Guanidine

In the first asymmetric synthesis of (-)-(S,S)-homaline, a symmetrical alkaloid isolated in the early 1970s, a key intermediate was compound 2 (Tetradhedron Lett. 2012, 53, 11191121). Provide reagents for converting compound 1 into compound 2. Ph CO2Me HN Cl Ph CO2Me N N3 Me Two steps 1 2

Nicotine is well known for its addictive characteristic in cigarettes. Interestingly, it has also been suggested to have potential therapeutic potential in central nervous system disorders such as Alzheimers disease, Parkinsons disease, and depression. However, due to the toxic side effects of nicotine, derivatives are being developed, such as compound 2, which shows much lower toxicity and exhibits analgesic (pain-inhibiting) properties (Bioorg. Med. Chem. Lett. 2006, 16, 20132016). Suggest an efficient synthesis of compound 2 from compound 1. N Cl HO2C N Cl N H 1 2

Halosaline is a naturally occurring alkaloid isolated from the herb Lobelia inflata. Its synthesis was recently completed by an azide reduction followed by an amide reduction (Org. Lett. 2007, 9, 2673 2676). The first of these steps was a ring contraction that converted a lactone to a lactam, shown here: O O N3 NH O OH 1) xs LAH 2) H2O Halosaline H2 Pd (a) Provide a structure for the alkaloid halosaline. (b) Why is it not possible to achieve the transformation above in just one step (rather than two), using LAH to reduce both the azide and the amide, in one reaction flask? (c) Draw a mechanism to account for the lactone-to-lactam ring contraction.

The formal synthesis of quinine in 1944 by Woodward and Doering was a landmark achievement (J. Am. Chem. Soc. 1945, 67, 860874). During their synthesis, the following compound was treated with excess methyl iodide, followed by a strong alkali solution of NaOH. Under these conditions, the initial Hofmann elimination product undergoes further conversion to afford a product with molecular formula C10H17NO2. Identify the structure of the product. 1) Excess CH3I 2) 60% NaOH N H H CO2Et NH2 O C10H17NO2

Piperazinone derivatives, such as compound 4, are being investigated for their potential use in the treatment of migraines as well as a variety of other diseases, including hypertension and sepsis. The following two-step synthetic procedure was developed as a general method for producing a variety of piperazinone derivatives (Tetrahedron Lett. 2009, 50, 38173819). Compound 1 is a readily available starting material that can be converted to compound 2 via an SN2 process. Reductive amination of compound 2 affords compound 3 which is short-lived and rapidly undergoes acid-catalyzed amide formation to the cyclic product 4, a piperazinone derivative. O Br H2N O N PhCH2NH2 NaBH3CN AcOH, heat 1 NaHCO3 DMF 2 H 4 3 OMe O OMe O (a) Draw the structure of 3 and explain why it is produced as a diastereomeric mixture. (b) Draw the structure of 4 and determine whether it will be produced as a mixture of diastereomers. Explain your reasoning.

Alkylating agents are compounds capable of transferring an alkyl group to a suitable nucleophile, and they represent an important class of anticancer agents. These agents can transfer an alkyl group to DNA (in a cancer cell), causing structural changes that ultimately lead to cell death. The product of the following transformation, which occurs via two successive substitution reactions, was designed to act as an anticancer alkylating agent (Tetrahedron Lett. 2004, 45, 58075810). Draw a structure for this product. N N N N NH2 O OSiEt Et3SiO 3 H2N EtO2C Br Br DBU C29H50N6O5Si2

Enaminoesters (also called vinylogous carbamates), such as compound 4 below, can serve as building blocks in the synthesis of nitrogen heterocycles. Compound 4 was prepared from compound 1 in a one-pot method (the entire transformation took place in one reaction vessel). Compound 1 was first converted to compound 2, but in the presence of methyl acetoacetate, compound 2 was further converted into imine 3, even without the introduction of an acid catalyst. Upon its formation, compound 3 then tautomerized to give enamine 4 (Tetrahedron Lett. 2005, 46, 979982). O OMe O H N N3 t-BuO O NH OMe O H t-BuO N O Pd H2 1 2 3 4 (a) Draw the structures of 2 and 3. (b) Imine- enamine tautomerization is very similar to keto-enol tautomerization. Draw an acid-catalyzed mechanism (using H3O+) for the conversion of 3 to 4. (c) The equilibrium for imine-enamine tautomerization generally favors the imine, but in this case, the enamine is favored. Give at least two reasons why the equilibrium favors enamine 4 over imine 3.

The following reaction was attempted during the total synthesis of crispine A, a cytotoxic alkaloid isolated from a Mongolian thistle (J. Org. Chem. 2011, 76, 16051613). Propose a plausible mechanism for the formation of compound 2 from amine 1. H3CO H3CO NH2 CO2CH3 O Cl [H3O+] H3CO H3CO N CO2CH3 1 2

During a recent study of epibatidine, a powerful analgesic isolated from an Ecuadorian poison dart frog, the investigators employed an interesting fragmentation reaction to access ring-opened analogues (J. Org. Chem. 1999, 64, 49664968). Propose a plausible mechanism for the following transformation: N OH N Cl Cl CO2Et CO2Et HO CF3 O NaBH3CN N N

Propose a plausible mechanism for the following transformation and justify the stereochemical outcome (J. Org. Chem. 1999, 64, 46174626): O N R CO2Me CO2Me Heat MeOH N R OH MeO