Chapter 12 1 CHAPTER 12 - textbooks.elsevier.com

Chapter 12 1

CHAPTER 12

1. Friedel-Crafts alkylation involves generation of a carbocation. When 1-chlorohexane reacts with aluminum

chloride, for example, a primary cation is formed. Primary cations are very unstable and subject to rearrangement

to the more stable secondary cation. Rearrangement of the cation occurs before its reaction with the benzene ring.

After rearrangement, the secondary cation reacts with benzene to form the arene. This facile rearrangement makes

it most difficult to prepare straight-chain arenes by this method. In the specific case of 1-chlorohexane,

rearrangement and reaction with benzene will give 2-phenylhexane as the major product.

2. There are two activating substituents on the aromatic ring, an OH and a CH2R. The oxygen has electron pairs

that can stabilize the Wheland intermediate for the Friedel-Crafts acylation reaction. The oxygen allows the charge

to be delocalized outside the ring, whereas the carbon group can stabilize the charge, but cannot delocalize the

charge outside the ring.

OH

NH2

COOH

Ac

H

O

NH2

COOH

Ac

H

H OH

NH2

COOH

Ac

H

see J. Org. Chem., 2000, 65, 2574vs.

3. The mechanism is taken from the Marcos', et. al. synthesis of ent-halimic acid - J. Org. Chem., 2003, 68, 7496.

Protonation of the vinyl ether, followed by addition of water, proton transfer, and loss of methanol leads to the

aldehyde product. The protonated aldehyde can be attacked by the distal C=C unit in the bicyclic system to form a

new ring and a carbocation. Loss of a proton in an E1-type reaction leads to the second observed product.

Copyright © 2011 Elsevier Inc. All rights reserved.

2 Organic Synthesis Solutions Manual

OMe

H

OMe OMe

H

OMe

OH2

OMe

H

O

H

OMe

H

OHMe

OH

OMe

H

OMe

OMe

OH

H

OMe

H

O Me

OMe

H

OH

H

OMe

OH

TsOH , aq acetone

– H+

– H+

+ H2O

– MeOH

4. Since NBS is a source of bromine, bromination of the allene unit proceeds by addition of Br+ to give a tertiary

cation. A Wagner-Meerwein rearrangement leads to the oxygen-stabilized cation, which loses a proton to give the

bromomethyl-ketone product.

OHCH2

MeMe

Br+

OH

MeMe

Br OH

MeMe

Br MeMe

OBr

see Tetrahedron: Asymmetry, 2000, 11, 3059

- H+

Wagner-Meerwein

5. The mechanism shown is that presented in the cited reference. Opening of the ring, with loss of HCl leads to the

cation, which eliminates to form a diene. Addition of the proton (from silica gel presumably) allows cationic

cyclization and loss of the proton to regenerate the aromatic ring.


Chapter 12 3

Cl

OMe OMe OMe

H+

OMe OMe OMe

see J. Chem. Soc., Perkin Trans. 1, 1992, 535

silica gel

6. The mechanism is taken from J. Am. Chem. Soc., 2003, 125, 1498. Note that the bond that migrates in the cation

intermediate is aligned anti rather than syn.

OH

OSi(i-Pr)3

O

OMe

OH

OSi(i-Pr)3

O

OMe

Me3Al

OH

OSi(i-Pr)3

O

OMe

Me3Al

OHHO

OSi(i-Pr)3

MeO

OH

OSi(i-Pr)3

O

OMe

Me3Al

OHO

OSi(i-Pr)3

MeO

Me3Al , CH2Cl2

7. See The Alkaloids, Vol. 2, Academic Press, 1952, p. 93; Ann., 1870, 153, 47. For a mechanistic evaluation of

this rearrangement, see J. Am. Chem. Soc., 1967, 89, 2464.



H2O

O

MeO

MeO

N MeH

H+

MeO

Me-O

HONHMe

CHO

O

MeO

MeO

N MeHH

MeO

O-Me

HOMeHNCHO

MeO

MeO

N Me

HO

H+H+

MeO

OH

HOMeHN

MeO

MeO

HON Me

– H2O

8. Initial reaction with nitrous acid converts the amine to a diazonium salt. Loss of nitrogen gives a cation, and

participation of the adjacent phenyl group leads to a phenonium ion. This ion is symmetrical, and addition of water

can occur from either carbon, leading to the mixture shown. The implication is that scrambling of the 14C label

will occur due to the intermediacy of this phenonium ion.

see J. Am. Chem. Soc., 1958, 80, 1447.

H3C NH2

CH3

H3C N2

CH3

H3C

CH3

OH2

H3C

CH3

OH2

CH3 = 14CH3

9. This mechanistic rationale is taken from a synthesis of (–)-lepadiformine Angew. Chem. Int. Ed., 2002, 41, 3017.


Chapter 12 5

OBn

C6H13

O

NHBoc

BnO

C6H13

ONHBoc

H+

N H

HCO2

C6H13

BnO

Boc

BnO

C6H13

HO

N

BocH

BnO

C6H13

OH2

N

Boc

N

HCO2

C6H13

BnO

Boc

N

HCO2

C6H13

BnO

Boc

BnO

C6H13

HO

NHBoc

–O2CH

N

HCO2

C6H13

BnO

Boc– H+

+ H+

– H2O

10. The Wolff-Kishner reduction proceeds under basic conditions and proceeds without rearrangement. The

Clemmensen reduction uses acid conditions. Eventually, protonation of the amine and loss of water leads to an

amino-ketone in its enol form. Reaction of the alkene moiety with acid and addition of the amine to give a more

stable five-membered ring leads to the product C. This addition probably proceeds via an organozinc moiety, as

shown.

N

O

N

OH

N

OH

HN

OH

H

N

O

HN

H

Zn

N

•

see J. Am. Chem. Soc., 1949, 71, 3089

11. The mechanism is taken from the cited reference. Initial coordination of BF3 to the epoxide oxygen and ring



opening to give the more sable benzylic cation, is followed by a 1,2-methyl shift, across the bottom face. Loss of

BF3 regenerates the carbonyl in the final product.

O

Ph

OTs

BF3•OEt2 , CH2Cl2

O

Ph

OTs

F3B

O

Ph

OTs

F3B

O

PhOTs

O

Ph

OTs

F3B0°C

– BF3

see J. Org. Chem., 2003, 68, 5917

12. The mechanism proposed for this transformation is taken from Org. Lett. 2003, 5, 333. Markovnikov addition

to the iminium in generates a new cation. Attack by the aromatic ring gives the phenonium ion intermediate, and

formation of the ketone unit regenerates the aromatic ring, and completes the rearrangement.

N

H Br

HO

HN

O

Br

HCOOH , toluene

reflux

N

H Br

HO

NH Br

HO

12

3

11

22

3 3

– H+

13.

(a)

OO

HO

OMOM

O

HN

O

Ph

J. Am. Chem. Soc., 2002, 124, 6552

(b)

O

OH

J. Org. Chem., 2002, 67, 6690

(c)

J. Am. Chem. Soc., 2003, 125, 1843

O

OMOM

Me

OTBS


Chapter 12 7

(d)

NMe

MeO

N

CO2Et

Bn

CO2Me

Org. Lett. 2002, 4, 3339

(e)

MeO O

OH

CO2H

J. Am. Chem. Soc., 2003, 125, 2400

(f)

see Tetrahedron Lett., 2000, 41, 1983

S

O

Tol

(g)

MsO

AcHN

J. Am. Chem. Soc., 2003, 125, 13486

(h)

O

Me

see J. Am. Chem. Soc., 2000, 122, 4020

(i)

OMe

CO2Me

H see J. Am. Chem. Soc., 1994, 116, 9912

(j)

MeO2C

N

O

O

see J. Am. Chem. Soc., 1999, 121, 3057

(k)

N

Ts

OTBS

H

Org. Lett., 2003, 5, 3427

(l)

BnO N

Bn

OSiMe2t-Bu

CO2Me

CbzHN

J. Am. Chem. Soc., 2003, 125, 6630

(m)

BrMe

O

J. Am. Chem. Soc., 2004, 126, 96

(n)

NCbz N

MeO

J. Am. Chem. Soc., 2004, 126, 706

(o)

see J. Am. Chem. Soc., 1961, 83, 3998especially pp 4002-4003

Br

(p)

MeO OH

H

O

Org. Lett., 2003, 5, 3931

(q)

Chem. Eur. J., 2002, 8, 853

(r)

O

Me

H

HMe

O

Me

H

H

see Org. Lett., 2000, 2, 1875

(s)

HO Ph(u)

J. Org. chem., 2002, 67, 2721

(t)

BzO OAc

OAc

OAc

NH

O

O

OMe O Org. Lett. 2002, 4, 1343

(u)

OH

H

OJ. Org. Chem., 2004, 69, 1744



(v)

N

SO2Ph

NH

CO2Me

see J. Org. Chem., 1998, 63, 2731

(w)

O

CN

(x)

O

O

O

O

Eur. J. Org. Chem., 2004, 209

(y)

see Tetrahedron, 1993, 49, 1649

O O

+

HO OH

(z)

N

H EtNMeO

Org. Lett. 2003, 5, 749

(aa)

THPO

OTHP

J. Org. Chem., 2003, 68, 6905

(ab)

N O

HMeO2C

H

MeO

MeO

Org. Lett. 2003, 5, 535

(ac)

Me

OH

OH

OHC

Org. Lett. 2003, 5, 4481

(ad)

MeO NH

Me

CO2Et

J. Org. Chem., 2003, 68, 6279

(ae)

NH

N•HCl

CO2H

J. Am. Chem. Soc., 2003, 125, 4541

(af)

NH

O

N Et

OOrg. Lett. 2003, 5, 3139

(ag)

N

Me

O

Ph

Br

CO2Et

EtO2C

J. Org. chem., 2002, 67, 2889

14. All of the following problems were taken from published syntheses. The sequences and reagents can be looked

up in those cases where they are not provided. If you devise your own synthesis and then check the literature, you

can compare your route to that published. More importantly, you may find that some of the steps you used were

tried in the literature and discussed. You may also devise a novel and useful alternative synthesis. In all cases,

your syntheses should be critiqued by and discussed with your instructor.

(a) See Chem. Pharm. Bull., 1975, 23, 2094.

(b) All reagents are taken from the cited reference. Initial benzylation of the amine used the reductive amination

with benzaldehyde and then reduction of the iminium salt with NaBH4. A Pictet-Spengler cyclization using the

acetal shown was followed by N-methylation. A final Dieckmann cyclization closed the last ring, and heating with

acetic acid/HCl gave decarboxylation to the final product.


Chapter 12 9

N

NH2

CO2Me

H

NMe

N

CO2Me

Ph

CO2Me

N

HN

CO2Me

H

Ph

N

OCH2Ph

H

HMe

NH

N

CO2Me

Ph

CO2Me

see Tetrahedron Lett., 2000, 41, 6299

a b

c d

(a) PhCHO , MeOH ; NaBH4 (b) (MeO)2CHCH2CH2CO2Me , TFA (c) NaH , MeI , DMF(d) NaH , MeOH/toluene , 110°C; AcOH/HCl , reflux

(c) All reagents are taken from Org. Lett., 2003, 5, 1123. Treatment of the free amine with base led to formation

of the lactam (2.5.C), which was reduced with lithium aluminum hydride to the amine (4.2.B). Formation of the

carbamate (7.3.C.iii) allowed a Pictet-Spengler cyclization (12.5.B), and reduction of the lactam as before provided

the amine ( -lycorane).

NH2 CO2t-Bu

O

O

O

O HN

H

H

O

O

O HN

H

H

O

O N

H H

H

O

O

O N

H

H

OMeO

O

O N

H H

H

a b c

d e

(a) NaOMe , MeOH (b) LiAlH4 (c) ClCO2Me , NEt3 (d) POCl3 , 90°C (e) LiAlH4 , THF

(d) All reagents in this sequence are taken from Org. Lett. 2002, 4, 1063. Conjugate alkylation with the

magnesium cuprate (8.7.A.vi) gave the alkylated ketone. Sequential enolate alkylation reactions with LDA

treatment to forma the enolate anion, followed by addition of an alkyl halide (9.3.A) gave the tri-alkylated ketone.

Flash vacuum pyrolysis induced the retro-Diels-Alder reaction (11.5.B), and alkylation of the ketone with the

organolithium reagent (8.5.C) generated from 4-bromo-1-butene and lithium metal (8.5.B) gave the final target.



O

H

H

OH

O

H

H O

H

H

O

a b c

d

(a) i-PrMgCl , CuI , ether (b) 1. LDA , THF-HMPA; allyl bromide 2. NaH , THF; MeI(c) FVP , 500°C (d) 4-bromo-1-butene , Li , ultrasound

(e) All reagents are taken from J. Org. Chem., 2004, 69, 3068. Two carbonyl units are protected as the dioxolane

derivatives (7.3.B.i), allowing the last ketone unit to be converted to the enolate anion with lithium

diisopropylamide (9.2), and trapping with the triflamide gives the vinyl triflate. Stille coupling (12.7.B) with

tributylvinyl tine, in the presence of palladium (0) leads to the diene, and a Lewis acid catalyzed Diels-Alder

reaction (11.6.A) gives the cycloadduct. Reduction of the aldehyde unit to the alcohol with diisobutylaluminum

hydride (4.6.C) was followed by removal of the dioxolane protecting groups (7.3.B.i). Treatment with methanolic

hydroxide leads to the intramolecular aldol condensation (9.4.A.ii) that gives the final target.

OO

OO

O

O

O

O

H

OH

OO

O

O

O

O

O

O

HCHO

O

O

O

O

O

O

O

O

O

H

OH

TfO

O

O

O

O

H

OH

O

O

a b c d

e f g

(a) (TMSOCH2)2 , 0.1 TMSOTf , CH2Cl2 , –78°C (b) 1. (TMSOCH2)2 , CH2Cl2 , –78°C 2. aq NaHCO3

(c) 1. LDA , THF , –78°C 2. PhNTf2 . –78°C rt (d) CH2=CHSnBu3 , Pd(PPh3)4, CuCl , LiCl, DMSO, 60°C

(e) CH2=C(Me)CHO , EtAlCl2 , CH2Cl2 , –95°C (f) 1. Dibal , ether , 0°C 2. Na2SO4•10 H2O(g) p-TsOH , H2O , acetone, reflux (h) NaOMe , MeOH; H3O+

h

(f) All reagents are taken from Org. Lett., 2003, 5, 2931. Treatment with base leads to a Dieckmann cyclization

(9.4.B.ii), and subsequent Wacker oxidation (12.6.A) gives the diketone. A second treatment with base leads to an

intramolecular aldol condensation (9.4.A.ii). When the conjugated ketone is heated with Zn/AcOH, reduction of

the enone system is accompanied by acid-catalyzed rearrangement (12.2.B) to the seven-membered ring product.


Chapter 12 11

O

O N

CO2Et

CO2EtO

ON

O

O

O N

O

O

O N

O

O

O

O N

O

a b

c d

(a) KOt-Bu , toluene; CaCl2 , DMSO (b) Pd+2Cu+ 2 , O2 . HCl , aq DMF (c) KOt-Bu , t-BuOH

(d) Zn , AcOH , 100°C

(g) All reagents are taken from the cited reference. An initial Wittig reaction with the appropriate benzylic unit

gives the alkene, which is hydrogenated. Treatment with the Lewis acid leads to Friedel-Crafts cyclization. A

Friedel-Crafts acylation leads to the ketone, which is treated with methyllithum and then acid to give the alkene. In

principle, the ketone could be treated with a Wittig reaction. Hydrogenation provides the isopropyl group in the

target.

CHO

MeO CH2PPh3 Cl

OMe

OMe

BuLiOMe

O

OMe

OMe

OMe

OH

OMe

see Tetrahedron: Asymmetry, 2000, 11, 781

a

b c d e

f

(a) H2 , 10% Pd-C , EtOH (b) BF3•OEt (c) acetyl chloride , AlCl3 (d) MeLi (e) p-TsOH , PhH (f) H2 , 5% Pd-C

(h) All reagents are taken from Org. Lett., 2002, 4, 631. Sharpless asymmetric epoxidation (3.4.D.i) gave the

epoxy-alcohol, which was converted to the tosylate, and then the tosyl group reduced to the methyl (4.2.C.vii), with

concomitant reduction of the epoxide to the alcohol (4.2.C.i). A Mitsunobu reaction (2.6.A.ii) converted the

alcohol to the amine, which was acetylated (7.3.C.ii), allowing a Pictet-Spengler cyclization (12.5.B) to the final

product.



MeO

Ar

OMe

OH MeO

Ar

OMe

OH

O

OMeOMOM

Me

MeO

Ar

OMe

N

Me

Me

MeO

Ar

OMe

OH

MeO

Ar

OMe

NH2

MeO

Ar

OMe

OTs

O

MeO

Ar

OMe

NHAc

Ar =

a b

c d e

f

(a) 5% Ti(Oi-Pr)4 , 6% D-DIPT , TBHP , CH2Cl2 , –20°C (b) TsCl , NEt3 , DMAP , CH2Cl2(c) LiAlH4 , ether (d) phthalimide , DEAD , PPh3 , THF (e) 40% aq MeNH2 , EtOH (f) AcCl , NEt3 , CH2Cl2 (g) POCl3 , 2,4,6-collidine, MeCN


Chapter 12 1 CHAPTER 12 - textbooks.elsevier.com

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