Chapter 4 1 CHAPTER 4 - Textbooks.elsevier.com

Chapter 4 1

CHAPTER 4

1. In each case, the Cram model is shown first and then the Felkin-Anh model, both in Newman projection. The

diastereomer that is predicted to be the major product is also shown.

(a)

OHOH

n-C3H7Hn-C3H7 n-C3H7H

H H

CRAM

n-C3H7

FELKIN-AHN

• H

HO

•

HHOO

•

O

•

(b)

Naphth

Me

OHNaphth

Me

OH

MeH

Naphth

NaphthMeH

Me

H H

NaphthCRAM

MeNaphth

FELKIN-AHN

Me

• H

HO

Me

•

HHO

O

Me

•O

Me

•

(c) In this case, reduction does not generate a chiral center, so the model used is irrelevant. Nonetheless, the

models are shown.

H

OH

MeO

PhHH

CH2OMeH

• H

HO

Ph

H

CH2OMe

O

H

•PhH

OH

CH2OMe

PhH

•

HHO

HPh

MeOH2CO

H

•

H

CRAM FELKIN-AHN

(d)

Copyright © 2011 Elsevier Inc. All rights reserved.

2 Organic Synthesis Solutions Manual

H

Et

O

Me

•

H

N

O

NO

CRAM

O

Me

•

Et

Et

H

Me

•H

OH

H Me

•

HHO

NO

N

O

Et

N

OMe

OHH

N

OMe

OH

H

FELKIN-AHN

2. (a) The conformation of this molecule is shown in the usual half-chair of a cyclohexenone derivative. Since

cerium borohydride will give selective 1,2-reduction, the main issue is stereochemistry. The bulky siloxymethyl

group on the bottom blocks approach from that face. Therefore, approach is from the top to give the

stereochemistry shown for the alcohol product.

N

O

EtO

Ts OSiPh2t-Bu

NaBH4•CeCl3

N

OH

EtO

Ts OSiPh2t-BuB

N

O

H

OSiPh2t-Bu

Ts

H

EtO

A

see Synthesis, 1999, 1889

via

(b) To predict the stereochemistry of this reduction, we can examine a 3D model of the ketone. The gem-

dimethyl unit as well as the other bridgehead methyl sterically block path A, but path B is relatively open and

predicts the major product. Alternatively, a LUMO map of the ketone shows a more intense blue color exposed to

face B, so delivery of hydride will be from that face.

Me

MeH

MeMe

OBnO

B

A

Me

MeH

MeMe

OBnOH

LiAlH4 , THF

0°C

see J. Org. Chem., 2000, 65, 7865

H H

(c) Coordination of the alcohol moiety with zinc borohydride modifies the conformation, as shown, to deliver


Chapter 4 3

hydride from behind. The result is the diastereomeric trans diol shown.

Me

H

OH

H

O

Me

HO

H

OZn

H4B BH4

Me

H

OH

OH

(d) The ethyl group effectively blocks one face of the azabicyclooctane ring. Delivery of hydride from the

direction of the arrow leads to the diastereomeric alcohol shown.

N

Et

O

Naphth

H N

Et

Naphth

HO H

H

3.

Me

CO2H

O MeO O

NaBH4 , CeCl3

see J. Org. Chem., 1998, 63, 1259

Cerium borohydride gives selective 1,2-reduction of the conjugated ketone, delivering hydride from the bottom

face to give the alcohol. This alcohol unit then reacts with the free carboxyl to form the lactone. Examination of

the 3D figure clearly suggests that attack from the top face (A) is blocked by both the methyl group and the -

CH2COOH group. The bottom face (B) is unencumbered, leading to the stereochemistry indicated for reduction of

the ketone to the alcohol and shown in the lactone. The LUMO map shows that attack from the bottom face, to

give the alcohol precursor required to give the lactone product, is slightly preferred.

A

B

topbottom

4. The first step is to look at the actual conformation of the steroid. Using the usual model for conjugated ketones

with R being the steroid ring, predictions can be made for reduction of the carbonyl. Diisobutylaluminum hydride



will coordinate to the carbonyl oxygen, restricting the angle from which hydride will be delivered. This

coordination leads to delivery of hydride via a complex that gives anti-Cram selectivity and generates the

diastereomer labeled . Selectride, however, does not coordinate, and delivery will be from the less sterically

hindered pathway (Cram selectivity), as shown, to give the -diastereomer.

see Tetrahedron Lett., 1985, 26, 69.

H

Me

Me

THPO

H

H

H

HO

Me

Me H

Me

R

MeH

• O

AlH i-Bu

i-Bu

Selectride

H

MeOH

R

Me H

•H

H

MeH

R

Me H

•HO

H

Me

R

Me H

•O

AlHiBu

iBu

Selectride

5. The first step of this reaction is reduction of the ketone unit to give an alcohol. Treatment with the basic reagent

tert-butoxide leads to an alkoxide product, as shown. With the tosylate unit properly positioned, a Grob-like

fragmentation is possible, leads to the aldehyde and the alkene units in the final product.

N

O

CO2t-Bu

Ph

H H

CO2Et

OTs

LiBEt3H

N

OH

CO2t-Bu

Ph

H H

CO2Et

TsO

KOt-Bu

N

O

CO2t-Bu

Ph

H H

CO2Et

TsO

N

CO2t-Bu

Ph

H H

CO2Et

CHO

see J. Org. Chem., 1999, 64, 4304

6. The reaction products shown are taken from the cited reference. The first step is epoxidation of the C=C unit

with meta-chloroperoxybenzoic acid. The Spartan model shown can be interpreted in several way: the methyl

group on the adjacent allylic carbon can provide steric hindrance, or the bridgehead methyl on the lower face could

block the reaction. In fact, the lower face is more hindered, and epoxidation occurs from the top face, in 81% yield.

Lithium borohydride opens the epoxide, this time from the lower face, and regioselectively at the less sterically

hindered carbon (see model) to give the alcohol shown.


Chapter 4 5

O

O

OSiMe2Thex

H

ANa2CO3

B

mCPBA

LiBEt3H , THF

O

O

OSiMe2Thex

H

O

O

O

OSiMe2Thex

H

OH

see J. Org. Chem., 2003, 68, 3831

7. Inspection of the 3D model shows that path A is blocked by the methyl group, so reduction with LiAlH4 occurs

by attack via path B, which gives the stereochemistry shown for the allylic alcohol. Both 1,2- and 1,4-addition are

possible, so LiAlH4 is used in ether at low temperature to maximize 1,2-addition. The second reaction is simply a

Mitsunobu reaction with the alcohol, first forming the benzoate ester with inversion of configuration, and the

treatment with methanolic KOH to give the requisite alcohol.


O

O H

LiAlH4 , ether –20°C

PPh3 , DEAD , PhCOOH then KOH/MeOH

OH

A

B

8. (a) Aluminum hydride coordinates effectively to the oxygen of the carbonyl. 1,4-Reduction demands

delivery of hydride to carbon via path B, whereas 1,2-reduction demands delivery via path A. Once bound to

oxygen, the distance between H and the terminal C of the C=C unit via path B is rather long, making delivery

difficult. Delivery via path A is facile due to the relatively short distance between the carbonyl C and H.



Coordination to oxygen therefore inhibits 1,4-addition and promotes 1,2-addition.

H

HH

H

O

AlH H

H

A

B

(b) L-Selectride is much more bulky than sodium borohydride. On approach to the carbonyl carbon, this steric

bulk will maximize steric interactions with the indane ring system and lead to greater selectivity relative to NaBH4.

Using the Cram model, the diastereomer shown is predicted to be the major product.

HH

O

O

HH

H

H •

OHHHH

H

(c) In this reaction, sodium transfers an electron to benzene to generate radical anion A. The proximity of the

single electron and the negative charge (2 electrons localized on that carbon) destabilize A due to electrostatic

repulsion. The resonance form (B) diminishes electrostatic interactions and is energetically favored. Transfer of

hydrogens to B leads to the final product, 1,4-cyclohexadiene.

• •

A B

(d) Transfer of an electron from sodium to anisole can generate two different regioisomeric radical anions, A

and B. The proximity of the negative charge to the electron donating OMe group destabilizes A, making B

energetically more favorable. This leads to the product shown. Similar reaction with benzoic acid leads to C and D

as the possible radical anions. In this case, the electron withdrawing carboxylate group stabilizes the adjacent

negative change in C, making it more stable than D where the charge is distal to the carboxylate group. For this

reason, C leads to the major product shown.


Chapter 4 7

OMe OMe OMe

CO2H CO2– CO2

–

A B

C D

OMe

CO2H

•

•

•

•

(e) Lithium aluminum hydride is a powerful reducing agent due to the charge distribution and polarity of the

Al—H moiety. It will reduce ester groups, acid groups, and carboxylate anion groups. Since LiAlH4 will reduce

both the ester and the acid, the product is a diol. Borane coordinates with the acid but not with the ester. It will

therefore transfer hydride only to the acid and not to the ester, and the acid is reduced and the ester is not. The

product is a hydroxy-ester.

(f) This reduction occurs via a six-centered transition state, as shown.

R

R

HN

NH

When the alkene is symmetrical and not polarized, electron density is readily transferred to hydrogen, leading

eventually to expulsion of N2, which drives the reaction. When the alkene is conjugated to a carbonyl, the electron

donating ability of the alkene is diminished, slowing the reaction by destabilizing the requisite six-centered

transition state. See J. Am. Chem. Soc., 1961, 83, 4302.

(g) In A there is a neighboring group effect where the OH group coordinates with zinc borohydride and delivers

hydride from the same face as the hydroxyl group. When the OH is blocked as the silyl derivative, zinc

borohydride cannot coordinate, and the usual steric effects lead to delivery of hydride from the face opposite the

OSiR3 group.

(h) This transformation is taken from J. Am. Chem. Soc., 2002, 124, 12416. Birch reduction of the naphthalene

unit containing the electron releasing OMe groups is expected to give the reduced product shown. Aqueous

hydrolysis converts the vinyl ether to the ketone, but the C=C unit in the ketone-bearing ring will move into the

other ring to form the aromatic ring, rather than into conjugated with the carbonyl. aromatization is the driving

force leading to the major product.



OMe

MeO

OMe

A

OMe

MeO

O

B

OMe

OMe

MeO

O

OMe

MeONa , EtOH , reflux

aq HCl reflux

9. The first transformation can be effected with Sn/HCl (Stephen reduction) or with LiAlH(Ot-Bu)3. The second

transformation can be effected with LiAlH4 or with LiBHEt3.

10.

(a)

H

OH

OO

Org. Lett., 2003, 5, 4741

(b)

CHO

(c)

O

O

(CH 2) 4O Piv

Me

HO

OPMB

OPMB

O PMBMe

MeOO TIPS

PMB = p-methoxybenzylPiv = pivaloyl

J. Am. Chem. Soc., 2003, 125, 12844

(d)

MeO

MeO CO2H

NH2

J. Org. Chem., 2002. 67, 8284

(e)

N

CO2t-Bu

CO2MeMeO2C

Org. Lett., 2003, 5, 999

(f)

Br

OMe

MeO

MeONHPMB

PMB - p-methoxybenzyl

Eur. J. Org. Chem., 2003, 1231

(g)

O

t-BuMe2SiO

O

OH

Org. Lett., 2002, 4, 1451

(h)

N Ph

HN

CO2t-Bu

MeO

Org. Lett. 2003, 5, 1927

(i)

N

N

HOH

MeBr

J. Org. Chem.,2004, 69, 1283


Chapter 4 9

(j)

NH

NHCO2t-Bu

CO2Me

J. Am. Chem. Soc., 2003, 125, 5628

(k)

t-BuMe2SiO

Me

OH

Me

see J. Org. Chem., 1999, 64, 4477

(l)

NHOCO2t-Bu

CO2Me

H

H

Org. Lett., 2003, 5, 447

(m)

NH

N H

J. Org. Chem. 2003, 68, 4523

(n)

O

O

PhMe2Si CH2OH

OH

J. Org. Chem., 2003 68, 2572

(o)

N

H

Me

CH3

OH

see J. Org. Chem., 1999, 64, 2184

(p)

OC15H31

CN

see Tetrahedron Lett., 2000, 41, 3467

(q)

N

O

H

OSiMe2t-Bu

Org. Lett. 2002, 4, 177

(r)

CHO

OSiPh2t-Bu

J. Am. Chem. Soc., 2002, 124, 4257

(s)

O OOHO

HO

Org. Lett. 2003, 5, 3357

(t)

O

H

I

OH

O

O

see J. Am. Chem. Soc., 1999, 121, 5176

(u)

OOMe

Me

OH

see J. Chem. Soc., Perkin Trans. 1 2000, 2645

(v)

OH OH

Ph

Me3Si

J. Am. Chem. Soc., 2004, 126, 2194 (w)

OMe

MeO

NO2

OMe

Br

J. Org. Chem. 2003, 68, 8162 (x)

NO

OHC

CHO

J. Org. Chem., 2004, 69, 1598

(y)

see Can. J. Chem., 1997, 75, 621

O

(z)

C13H27

OSiMe2t-Bu

NHAc

OH

see Tetrahedron Lett., 2000, 41, 2765 (aa) see J. Org. Chem., 2002, 67, 4127

TBSOO

O

O



(ab)

Ph Ph

see Synlett, 1999, 182 (ac)

N N

CH2OH

CH3

Cl CO2Et

J. Am. Chem. Soc., 2002, 124, 9476 (ad)

t-BuMe2SiO

t-BuMe2SiO OH OH

J. Am. Chem. Soc., 2002, 124, 12806

11. In each case a synthesis is shown. These are not necessarily the only approaches. It is very likely there are

many approaches for several of these questions.

(a) The acid hydrolysis of the vinyl ether to the ketone may also convert the methyl ester to the acid. If this

occurs, an esterification step (thionyl chloride; methanol) would be required. Mild acid hydrolysis of the vinyl

ether should be possible, however.

Me

CO2Me

MeO

Me

CO2Me

MeO

Me

CO2Me

O

Me

CO2Me

O

O

O

ab c (a) Na , NH3 , EtOH

(b) aq H+ (c) O3 ; H2O2

(b) The first step requires a chain extension and converting the alcohol to its tosylate introduces the requisite

leaving group, allowing a subsequent reaction with NaCN to give the corresponding nitrile. DIBAL-H reduction of

the nitrile gives the aldehyde.

HO

OPMB

NC

OPMB

OHC

OPMB


a b

(a) 1. TsCl , pyridine 2. NaCN , DMSO (b) DIBAL-H , THF

(c) All steps in this synthesis are taken from Org. Lett., 2002, 4, 1379. Bromination of the allylic alcohol (2.8)

and SN2 displacement with cyanide gives the nitrile (2.6.A.i). Basic hydrolysis to the carboxylic acid, and

esterification with diazomethane (2.5.C; 13.9.C), was followed by selenium dioxide oxidation to the aldehyde

(3.8.A). Reduction of both the ester and aldehyde with LiAlH4 gave the diol (4.2.B), and selective chlorination of

the allylic alcohol with N-chlorosuccinimide (2.8) gave the final target.


Chapter 4 11

OH Br CN

CO2Me

OHC

CO2Me

OH

OH

CO2H

Cl

OH

a b c d

e f g

(a) PBr3 t-BuOMe (b) KCN , DMSO (c) 25% KOH , MeOH (d) CH2N2 , ether (e) SeO2 , t-BuOOH , CH2Cl2 (f) LiAlH4 , THF (g) NCS , Me2S , CHCl2

(d) The Wittig olefination step is discussed in chapter 8.

OH

OMe

O

OMe

OH

OMe OMe

OHC

OMe

Oa b c d

e f (a) NaH ; MeI (b) Na , NH3 , EtOH (c) H2 , Pd (d) O3 ; Me2S (e) Ph3P=CH2 (f) LiAlH4

(e) All reagents are taken from the cited reference. The first reaction reduces the ester unit to an alcohol. This

is followed by conversion to a tosylate that allows Super-Hydride reduction to give the methyl group. The O-SiR3

unit is cleaved with aqueous acid to give the corresponding alcohol (see chap. 7, sec. 7.3.A.i). The primary alcohol

is then converted to the aldehyde by a Swern oxidation (see chap. 3, sec. 3.2.C.i).

CO2Me

OSiMe2t-Bu

CH2OTS

OSiMe2t-Bu

Me

O

H

CH2OH

OSiMe2t-Bu

CH3

OSiMe2t-BuCH3

OH


ab

c d

(a) DIBAL-H , toluene , –78°C (b) TsCl , DMAP , NEt3 (c) LiEt3BH , THF (d) AcOH , aq THF (e) DMSO , (COCl)2 , NEt3

e



(f) All reagents are taken from the cited reference. Initial reduction of the acid to the alcohol was followed by

treatment with tosic acid. This led to an internal transesterification to the lactone, and conversion of the dioxolone

to the alcohol. Treatment with the dimethyl acetal of formaldehyde led to the ether shown (a MOM group - see.

chap. 7, sec. 7.3.A.i), and DIBAL-H reduction converts the lactone to a lactol.

CO2H

OO

O

OO

O

OH

OO

HO

OO

OO

OHO

OO

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

a

b c d

(a) BH3 , THF ; H3O+ (b) p-TsOH , CHCl3 (c) CH2(OMe)2 , P2O5 (d) DIBAL-H , CH2Cl2

(g) All reagents are taken from the cited reference. Initial reduction of the ester unit (using DIBAL-H) gives the

allylic alcohol. To insert the proper stereochemistry for the new alcohol unit, Sharpless asymmetric epoxidation

using (-)-DIPT (see Sec. 3.4.D.i) gives the epoxide and selective reduction of the less sterically hindered carbon of

the epoxide with Red-Al gives the final product.

CO2Et

OO SiMe3

O

O SiMe3

OH

OH

OO SiMe3

OH

OO SiMe3

OH

O


a b

c(a) DIBAL-H , CH2Cl2 , –78°C (b) (–)-DIPT , t-BuOOH , Ti(OiPr)4 (c) Red-Al , THF

(h) A Friedel-Crafts acylation inserts the ketone moiety, and the Wolff-Kishner reduction removes the carbonyl.

Catalytic hydrogenation reduces not only the benzene ring but also the nitro group in a single step.

O n-C3H7

n-C3H7n-C3H7

NO2

n-C3H7

NH2

a

b

c d

(a) butanoyl chloride , AlCl3 (b) N2H4 , KOH (c) HNO3 , H2SO4 ; separate ortho product(d) excess H2 , Ni(R)

Section 12.4.D p 1090

(i) All reagents were taken from Eur. J. Org. Chem., 2003, 4445. Reduction of the acid with borane (4.6.A) was


Chapter 4 13

followed by bromination with carbon tetrabromide and triphenylphosphine (2.8.A).

NCl OMe

CO2H

NCl OMe

HO

NCl OMe

Br

a b(a) BH3•SMe2 , B(Me)3 , THF (b) CBr4 , PPh3 , benzene

(j) All reagents are taken from the cited reference. The first problem is how to remove the OH group. If the

OH is first converted to a tosylate, Finkelstein exchange (chap. 2) generates an iodide that can be reduced with tin

hydride. The ester is reduced to an alcohol with LiBH4, and aqueous acid converts the dioxolane unit (a ketal) to

the carbonyl (see chap. 7, sec. 7.3.B.i). The final step is an oxidation. Several methods can be used from chap. 3,

sec. 3.2, but the Dess-Martin periodinane reagent was used in this citation.

N

OO

O

OMe

EtO2C

OH

N

OO

O

OMe

EtO2C

OTs

N

OO

O

OMe

EtO2C

N

O

OMe

OHC

O

N

O

OMe

HOH2C

O

N

OO

O

OMe

HOH2C

see J. Am. Chem. Soc., 1999, 121 , 7778

a bc

de

(a) TsCl , DMAP (b) 1. NaI , acetone 2. Bu3SnH , AIBN (c) LiBH4 , THF (d) HCl , aq. AcOH (e) Dess-Martin

(k) Hydrogenation with a Lindlar catalyst sets the cis alkene geometry.

H H Bu H Bu Bu Bu Bua b

(a) NaNH2 ; n-C4H9-I (b) NaNH2 ; n-C4H9-I (c) H2 , PdCO3 , quinoline

c

12. In each case a synthetic solution is shown. There are other approaches based on other disconnections. The

Aldrich catalog (2000-2001) was used as a source for the starting material for convenience. There are, obviously,

other sources of chemicals.



(a) An attractive starting material is the commercially available benzylacetone at $95.40/Kg, but it has more than

the required five carbons. One more disconnection leads to acetone, which can be converted to benzylacetone via

enolate alkylation (see Sec. 9.3.A). Acetone is available from Aldrich ($18.30/L) and has less than five carbons.

The Wittig olefination step(a) is discussed in Section 8.8.A.

O Me

Me

MePh

Br

Br Me

O Ph

Me

MePh

Me

MePh

Me

O Ph

Me

MePh

Br

Br Me

O Me

Mebenzylacetone

b c

(a) LiN(iPr)2 ; BnBr (b) Ph3P=CHMe (b) Br2 , CCl4

a

acetone

(b) The starting material is 3-methyl-2-butanol at $43.10/100 mL. Initial conversion to a mesylate allows an SN2

reaction with the anion of 1-propyne. The alcohol could also be converted to a bromide using PBr3 or a similar

reagent. Lindlar reduction of the alkyne leads to the cis-alkene.

OMsOH

OH

a b c

(a) MeSO2Cl , NEt3 (b) MeC C– Na+ , DMF (c) H2 , Pd-BaCO3-quinoline (Lindlar)

(c) The requirement that the starting material be five carbons or less makes this a very cumbersome synthesis. The

point of this exercise is first to give practice for various reactions but also to show that setting arbitrary starting

material requirements can have profound consequences. A shorter approach, for example, would use phenetole

(ethoxy benzene) and Birch reduction. In the synthesis shown, 2-ethoxy-propanoic acid was not found to be

commercially available (someone probably sells it if sufficient time was taken to find a source), but the expensive

-propiolactone at $76.20/5 mL can be opened with ethanol (transesterification) to give the requisite alcohol-ester.

Wittig olefination (see Sec. 8.8.A) can be done with a carboxyl substituent.


Chapter 4 15

EtO2C NHBuO

O

EtO2CCO2H

O

EtO2C CHO EtO2COH

O

O

EtO2C

CO2H

O

O

EtO2COH

EtO2C CHO

EtO2CCO2H

O EtO2C NHBuO

O EtO2C

CO2Ha b c

d e

(a) EtOH , H+ (b) PDC , CH2Cl2 (c) Ph3P=CHCH2CO2– Na+ (d) MCPBA (e) BuNH2 , DCC

(d) This synthesis begins with benzene at $31.00/L and bromination followed by reaction with cuprous cyanide

gives benzonitrile. Rosenmund reduction gives benzaldehyde (remember that we had to begin with material

containing only 6 carbons). A Wittig olefination (see Sec. 8.8.A) gives styrene and a radical HBr addition gives the

primary bromide. An SN2 displacement with cyanide allows selective reduction to the aldehyde.

PhCHO

PhBr PhCHO

PhCHO Ph PhBr

PhCN

PhH PhBr PhCN PhCHO

PhH

PhCHO

d e f g

d) Ph3P=CH2 (e) HBr , ROOR (f) NaCN , DMF (g) LiAlH(O t-Bu)3

a b c

(a) Br2 , FeBr3 (b) CuCN , heat (c) Sn , HCl

13. (a) NaBH4 (b) Na , NH3 , EtOH (c) LiAlH(Ot-Bu)3 - some diol will also be formed with virtually any

reagent (d) NaBH3CN , pH 7

(e) The first step requires reduction of the ketone to an alcohol, and the mild reagent NaBH4 was used. The second

step uses NBS to form a bromonium ion, which is opened by the proximal alcohol unit to give the bromo-ether

shown. Both reagents used here were taken from the cited reference.

N

O

CO2Bn

N

CO2Bn

OBr


1. NaBH4 , MeOH2. NBS , MeCN



(f) LiAlH4 will reduce the ester to the alcohol, the azide to the amide, and the lactam to the cyclic amine. See J.

Org. Chem., 1996, 61, 4572.


Chapter 4 1 CHAPTER 4 - Textbooks.elsevier.com

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