Chapter 4 1

CHAPTER 4
1. Give the major product for each of the following transformations involving conversion of a
carboxylic acid or a derivative into another acid derivative.
1.
SiMe3
N(CH2Ph)2
O O O
Et
(a) (b) H (c) OMe
O N MeO
O
O
Cl
OMe
Et
see J. Org. Chem. 1999, 64, 4980 see J. Org. Chem. 1999, 64, 7586 see Tetrahedron Lett. 2000, 41, 733
OMe O
O H
NEt2 Me N Ph
(d) (e) (f) (CH2)9
Cl NHi-Pr
MeO O Me
OMe
see Tetrahedron Lett. 2000, 41, 1975 see J. Am. Chem. Soc. 1994, 116, 9921 see J. Org. Chem. 1999, 64, 2450

O
O O MeO O
(g) N (h)
H O
N
O
O

see J. Org. Chem. 1999, 64, 3736 see J. Am. Chem. Soc. 1994, 116, 9921
2 Organic Synthesis Solutions Manual

2. Offer a mechanistic explanation for the following transformation.

2. See Tetrahedron Lett. 1997, 38, 3469. When drawn in a form that approximates the three-dimensional
shape it is clear that the cyclobutanone unit flattens the tricyclic system. Protonation of the glycol unit is
followed by acid-catalyzed addition of methanol to the ketone. A Grob-like fragmentation leads to
formation of the methyl ester unit and a cation. This cation traps water and with proton transfers loses
ethylene glycol to form the ketone unit found in the final product.

O O
O
O MeOH , 1N HCl OMe
H H
O RT H O
CO2Me - ethylene glycol
H - H+

O H O H
O O
O OH
OMe
H O
H O
H H O
OMe
+ H+ H
-H+;+H +
H O
H O
H H O
H O
O H O OH2
+ MeOH; - H+ O
O H+ transfer OMe
OMe
H + H2O H O
H O
H H
H
 Chapter 4 3

3. Suggest a reasonable mechanism for this reaction.

3. Initial attack of hydroxide leads to opening of the oxazolone ring, and the nitrogen attacks the epoxide,
forming the indolizidine ring and generating an alkoxide. Protonation to give the alcohol is followed by a
second attack of hydroxide on the carbonate ester. Carbonic acid is formed as the alkoxide is released in
an acyl substitution reaction. The carbonic acid decomposes to water and carbon dioxide and protonation
by ethanol gives the final product.

O O
H O H OH
OBn OBn
EtOH
OBn OBn
N N
N N
O O O O
OH O
O OH O O
H OH HO OH HO
O OH H
H
- EtOH
HO OBn HO OH
N OBn OBn
N N
O OH OH
O

HO O see J. Org. Chem. 2000, 65, 9129

4. Explain why these two saponification reactions lead to different products (ring closed vs. ring
opened).
4. Saponification gives a hydroxy-acid in both cases. Under acidic conditions, formation of a five-
membered ring is energetically very easy, and the equilibrium in this acid-base reaction favors closure to
the five-membered ring. In this case, the energy demands on the ring are low (little torsion strain or
Baeyer strain). In the second case, once opened, ring closure would regenerate an eleven-membered ring.
Eleven-membered rings are inherently high in transannular strain, and the transition state leading to ring
closure would assume the conformation of the eleven-membered ring. The strain for regeneration of the
eleven-membered ring would therefore be very high, inhibiting its formation.

5. Inspection of Section 4.5.3 suggests that the Mukaiyama reagent gives better yields of lactone
with simple ω-hydroxy acids than the Corey-Nicolaou reagent. Offer an explanation that accounts
for this observation.
5. The Mukaiyama reagent simply activates the carbonyl to a greater extent than the Corey-Nicolaou
reagent. The Mukaiyama reagent reacts with the alkoxy oxygen of the carbonyl group displacing the
ortho chloro group. The ammonium salt coordinates the hydroxyl, and formation of the lactone generates
a pyridone. The equilibrium favoring formation of the pyridone is better than that favoring formation of
the thiopyridone product produced by the Corey-Nicolaou reagent. In addition, the Corey-Nicolaou
reagent depends upon protonation, whereas the Mukaiyama reagent is an ammonium salt that does not
require external protonation.
4 Organic Synthesis Solutions Manual

6. Give the major product of each reaction.

6. Both reactions are macrocyclization reactions that generate a macrocyclic lactone. The circled free
OH reacts with the carboxylic acid unit to form a lactone using the Yamaguchi protocol for (a) and (b).

BnO
O TBSO Me
O Me
Cl
HO Me O O
Cl
1. Cl
Me O OBn
Me Cl
(a) Me
TBSO NEt3 ,THF , 0 °C
Me CO2H 2. DMAP , toluene , RT
N S Me
Me
S see Org. Lett. 2000, 2, 2575 N

Me Me
HO2C

O O OMe

MeO
1. KOH , MeOH
(b) O O
O 2. 2,4,6-trichlorobenzoyl chloride
DMAP , NEt3 O
see J. Am. Chem. Soc. 2002, 124, 1664 O

OH O

7. Show a synthesis for the following retrosynthesis.

7.
OMOM OH OMOM O OMOM
OH
a b c

(CH2)10 (CH2)10 (CH2)10 (CH2)10

OH CO2H O
CH2
OMOM OMOM OMOM
O
d e g
f
(CH2)10 (CH2)10
(CH2)10 (CH2)10

(a) NaH ; MeOCH2Cl (b) 9-BBN ; H2O2 , NaOH (c) PDC (d) Ph3P=CH2
(e) 9-BBN ; H2O2 , NaOH (f) CrO3 , H+ (g) i. BF3 ii. Mukaiyama reagent

8. The reaction of sodium cyanide and cyclohexanone gives a poor yield of the cyanohydrin. You
attend a lecture and learn that silicon compounds (e.g., Me3SiCl) react with methoxide to form
Me3SiOMe. In another flash of inspiration, you mix cyclohexanone, KCN, and Me3SiCl. What
product do you anticipate will be formed from this reaction? Draw a reaction sequence that leads
to your product.
O O– OSiMe3
KCN ClSiMe3
8. CN CN
 Chapter 4 5

9. The reaction of heptan-3-one and butan-1-amine leads to the corresponding imine. Draw it. It
order to convert this imine back to heptan-2-one, you heat the imine with aqueous acid. Write out
the complete mechanism for conversion of this imine back to heptan-3-one under these conditions.
9.
H Bu
H Bu N
N-Bu H + OH2 -H+
N

OH2
H H
Bu H Bu H
N H+ -H+ O
N -H2NBu O

OH OH

10. Molecule A (called talaromycin B) is a natural product that contains a ketal unit. Molecule B is
a derivative of talaromycin B. Suggest an acyclic precursor that can be transformed to B by a
simple chemical reaction. Show that reaction and briefly discuss why B could be formed from this
precursor.
10. From a synthetic viewpoint, the ketal is formed from the ketone shown. Note that any synthesis must
account for the absolute stereochemistry of the groups in the acyclic ketone in order to generate the ketal
with the correct stereochemistry. Note also how the (R)/(S) configuration changes when the ring system
is opened to the cyclic ketone since there are now two OH units. The molecule is drawn in the same
perspective as B to show the stereochemical relationships, and then again in the extended conformation.

H HO H PhH2CO O

O HO
H O PhH2CO
O H
OH OH
PhH2CO H OCH2Ph PhH2CO H OCH2Ph
B

11. When cyclohexanone is treated with an acid catalyst in the presence of both propane-1,3-diol
and octane-1,8-diol, one product predominates via reaction of only one of the diols. Draw this
product and briefly discuss your choice (specifically why it works and the other does not).
11. Formation of the ketal from propane-1,3-diol requires formation of a stable six-membered ring,
whereas formation of the ketal from octane-1,8-diol requires formation of a high energy nine-membered
ring. The transannular strain inherent to a nine-membered ring poses an energy barrier that is too high for
formation of this ketal.
O O

O O
6 Organic Synthesis Solutions Manual

12. Give the product formed from each of the following reactions:
12. The major product or products are shown. No mechanisms are provided.
(a) pyrrolidine , cat H+ N
O

O
(b)
NH2 N
cat H+

CHO HO OH O
(c)
cat H+
O
Ph Ph Ph Ph
OH Ph
(f) Ph
cat H+ BuO OBu
O
O NH
(g) O N O
cat H+

O
O O H2O + HOCH2CH2OH
(h)
cat H+

13. Laetrile (A) is a compound that was believed to be effective against cancer. What do think will
happen to A when it is ingested and hits the 6 N HCl in your stomach. Draw a mechanism and the
products.
13. Acid hydrolysis will lead to the sugar shown, and benzaldehyde. Along the way, cyanide is released
as a leaving group. Laetrile may kill cells by exposing them to deadly cyanide, but it is unlikely there is
any selectivity for cancerous cells versus normal cells.
COOH COOH H COOH CN
CN O OH OH2
HO O O H+ O O CN HO
HO
HO HO HO
HO Ph HO Ph HO Ph
A

CN -H+ H
H2O -H+ HO CN – –CN H O
O
H Ph
Ph Ph Ph

14. In the Bayer–Villiger reaction of nonan-4-one to butyl pentanoate with trifluoroperoxyacetic

acid, a large excess of sodium acetate is sometimes added as a buffer. Explain why this is necessary.
14. The byproduct of the reaction is the strong acid trifluoroacetic acid. The buffer is added to prevent
this acid from reacting with the product and causing unwanted secondary reactions.
 Chapter 4 7

15. Briefly explain why saponification of 1,1-dimethylethyl butanoate is much slower than the
saponification of methyl butanoate.
15. The adjacent methyl groups sterically hinders approach to the carbonyl carbon in 1,1-dimethylethyl
butanoate relative to methyl butanoate. Since reaction with hydroxide or with water under acid conditions
requires a nucleophilic attack at the acyl carbon, if that carbonyl is sterically hindered the reaction will be
much slower.

16. An attempt to convert ethyl butanoate to isopropyl butanoate was done as follows. Ethyl
butanoate was dissolved in methanol and treated with 5 equiv of isopropyl alcohol (propan-2-ol)
and an acid-catalyst. When the reaction was analyzed, there was essentially no ethyl butanoate,
<10% of isopropyl butanoate and ~ 90% of another product. What is it and describe how it might
be formed. How can you modify this procedure to obtain isopropyl butanoate?
16. The product was methyl butanoate, from reaction with methanol. Methanol is more reactive than
isopropyl alcohol, and only a five-fold excess of isopropyl alcohol is probably insufficient to compensate
for the difference in rate. The solution is to use isopropyl alcohol as the solvent, with no methanol.

17. When butanoyl chloride reacts with ethanol, in benzene solvent, it is common to add
triethylamine to the reaction. What purpose does this serve and how does it help?
17. The second product in this reaction is HCl. Triethylamine is added as a base. Reaction of
triethylamine with HCl gives triethylammonium chloride (HEt3N+Cl–). Removing one product in this
way drives the reaction towards the desired ester product. The water-soluble ammonium salt is easily
removed from the ester by simply washing with water.

18. Give the major product for each of the following reactions.
18. The major product or products are shown. No mechanisms are provided.
1. SOCl2 O
(a) CO2H
2. Me2CHOH , NEt3
O
1. aq. NaOH then
neutralize with H3O+
(b) 2. Me(Bu)NH NMe(Bu)
CO2Me 3. 200 °C
O
CO2H 1. PCl5
2. butanoic acid
(c) O

O O O
1. EtOH , NEt3 O
2. MeOH , cat. H+
(d) Cl OMe
8 Organic Synthesis Solutions Manual

1. SOCl2
O 2. ammonia
(e) CN
3. P2O5
OH

OH O
(g) CO2H
DCC O

diethylamine , reflux
(h) CO2Me CONEt2

EtOH (solvent)
(i)
cat H+ , reflux
CO2H CO2H CO2Et CO2Et

1. 6N HCl
(j) CN CO2Et
2. EtOH , cat H+

19. Give the major product for each of the following reactions:
19. Give the major product for each of the following reactions.
O O
+
EtOH , cat H
(a)
O OEt

OH
O O
1-Aminobutane
(b)
O Reflux
N-Bu

O
H3O+
(c) AcO CO2Me
O
O O
MeNH2
(d) O
Heat
N-Me

O O
 Chapter 4 9

20. Give the major product for each of the following:

20 The major product or products re shown. No mechanisms are provided.
OH O
1. MeMgBr , ether

(a) + 2. aq H+
N 3. cyclopentanecarboxlic acid H
H CrO3Cl H+ catalyst
HO
MeO
excess H2O in THF
(b)
cat H+ O
O
O
1. SOCl2
2. Mg , ether
OH
(c) 3. 0.5 ethyl butanoate
4. H3O+

1. SOCl2
(d) CO2H CO2CHMe2
2. propan-2-ol

OH O
1. CrO3 , H2SO 4, aq acetone
(e)
2. SOCl2
3. Ph2CuLi , THF , 0 °C Ph
1. SOCl2 O
(f)
2. MeNH2
CO2H
NHMe

(g) 1. SOCl2
SO2H SO2OCH2CHMe2
2. Me2CHCH2OH
O
1. KCN , DMF
2. H3O+ , heat
(h) Br NMe2
3. Me2NH , DCC

Me3CO3H O
(i) O
O

O O
Me3CO3H
(j) + MeCO2H
O
10 Organic Synthesis Solutions Manual

21. Give the complete mechanism for the following transformation:

21.
OH
O H OH + OH2 OH
+ H+ O - H+ + H+
R NMe2
NMe2 R NMe2 O R NMe2
R NMe2 OH
H H

OH H
-NHMe2 OH - H+ O
Me O
R N Me
HO R OH R OH OH
H

22. Give the major product of each reaction.

22.

N3 heat O
C
(a) N
O
O
(b) 1. NH2OH
O
2. H2SO 4 NH
O O
HN3 , H+
(c) N
H

CO2Me NH2
1. NH3 , heat
(d)
2. NaOBr

HO O
N H H
N
H
p-TsCl , NEt3
(e)
cat DMAP , CH2Cl2 OTIPS
OTIPS MeO H
H OMe Org. Lett. 2000, 2, 2373
MeO OMe
N-OH H O
N
1. TsCl , NaH , THF
(f) 2. AlCl3 , CH2Cl2
Org. Lett. 2014, 16, 2373

Me CO2Et MeO Me CO2Et

MeO
 Chapter 4 11

BnO OMe
OBn OBn
2 ClSO3H , -30 °C
(g)
CH2Cl2 N Org. Lett. 2012, 14, 3604
O
N3
OMe Bn O
O

1. (COCl)2 O
O
(h) O 2. NaN3 , heat O
N OMe
N OMe
J. Am. Chem. Soc.
O 2011, 133, 17634
O
H2N
HO2C