Chapter 12

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

O
Ac
H
COOH

NH 2

OH
Ac
H
COOH

NH2

Ac
vs.

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

H
COOH
NH2

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.

Organic Synthesis Solutions Manual

OMe

OMe
OMe

+ H2 O

TsOH , aq acetone
H

H
H
O
OMe

OMe

Me

O Me
OMe

OMe

MeOH
H

H
OH2

H
OH

OMe

OH

OHMe

OMe
H+

OMe

OMe
OH

OH

H+

H
O
H

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.

OH

OH
CH2

Me

Me

Br

OH

Me

Br

Me

-H

Br +
Me

Me

WagnerMeerwein

Me

Me
O
Br
see Tetrahedron: Asymmetry, 2000, 11, 3059

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

OMe

OMe

OMe

OMe

OMe

OMe

H+

silica gel
Cl

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

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

OMe

Me 3Al O
Me 3 Al , CH2 Cl2
OSi(i-Pr)3

OH

OMe

Me3 Al O
OSi(i-Pr)3
HO

Me 3Al O

OH

OMe
OH

OSi(i-Pr) 3

HO

OH

OMe

OSi(i-Pr)3

MeO

OSi(i-Pr) 3

MeO

OSi(i-Pr) 3

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.

Organic Synthesis Solutions Manual

MeO

MeO
H

H2 O

H O

H
N Me

MeO

HO

HO

H
N Me

MeO

MeO

MeO

N Me

MeO

MeO

MeO

HO

CHO
NHMe MeHN HO

N Me

MeO
H+
MeO
H2 O

H
CHO

MeHN HO

O-Me

Me-O

OH

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.
OH 2
H3 C

NH 2
CH3

H3 C

N2

H3 C

CH3

H3 C
CH3

OH2
CH3

CH3 = 14 CH 3

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

Chapter 12

NHBoc

NHBoc
O

BnO

BnO

OBn
NHBoc
C6 H13

H+

HO

C 6 H13

C6 H13

Boc
N H

BnO

BnO

H
HO

Boc
N

BnO
OH2

+ H+

HCO 2

C 6H 13

C 6H 13

C 6 H13

BnO

BnO

BnO

N
Boc

H 2O

N
Boc

N
Boc

O 2CH

Boc
C 6 H13

HCO2

HCO2

HCO2

C6 H13

C6 H13

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.

OH

OH

N
O

Zn

OH

N
H

N
H

N
H

N
H

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

Organic Synthesis Solutions Manual

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.
OTs

OTs

OTs

0C

F3B

OTs

OTs

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

Ph

BF 3

Ph
F3 B

Ph

Ph
F3B O

BF 3OEt2 , CH2 Cl2

Ph
O

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.

H Br
N

H Br
N

HCOOH , toluene

reflux

HO

HO

H Br
N

Br

HO 1

H
N

H+

O
1

13.
OMOM
HO
H
N

(a)

Ph

(b)

(c)

O
O

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

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

Me
OTBS

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

Chapter 12

CO2 Et

(d)
N
Me

MeO

CO2 H
O

(e) MeO

N Bn

(f)

O
S Tol

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

CO2 Me
Org. Lett. 2002, 4, 3339

see Tetrahedron Lett.,

2000, 41, 1983

AcHN

(h)

(g) MsO

(i)

Me

CO2 Me
O

Me

O
H

J. Am. Chem. Soc., 2003,

125, 13486

MeO2 C

CO2 Me

O
OTBS

(j)

(k)

see J. Am. Chem. Soc.,

1999, 121, 3057

(l) CbzHN
N
Ts

OSiMe2 t-Bu

Bn

MeO

(m)

(n) Cbz

Br

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

Br

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

MeO

J. Am. Chem. Soc., 2003,

125, 6630

BnO

Org. Lett., 2003, 5, 3427

Me

see J. Am. Chem. Soc.,

1994, 116, 9912

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

OH

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

(q)

(r)

(p)

H
H

H Org. Lett., 2003, 5, 3931

Me

Me H
H

Chem. Eur. J., 2002,

8, 853

Me
see Org. Lett., 2000, 2, 1875

OAc
BzO

(s)

(u) HO

(t)
Ph

J. Org. chem., 2002,

67, 2721

OAc

O
O

(u)

OAc
NH
OMe O Org. Lett. 2002, 4, 1343

J. Org. Chem., 2004,

69, 1744

Organic Synthesis Solutions Manual

CO2 Me

(v)

(y)

(x)

NH

(w)

N
SO2 Ph
see J. Org. Chem.,
1998, 63, 2731

O
O

CN

(z)

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

(aa)

+
HO see Tetrahedron, OH
1993, 49, 1649

(ab)

MeO
MeO

MeO

H N
MeO 2C

N
Org. Lett. 2003, 5, 749

(ae)

OH

(ac)
O
H

Me

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

(ad)

Me
MeO

OH

Org. Lett. 2003, 5, 4481

CO2 Et

N
H

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

(af)

NHCl
N
H
J. Am. Chem. Soc., 2003,
125, 4541

THPO

OHC

Org. Lett. 2003, 5, 535

CO2 H

OTHP

Et

N
H

Et

CO2 Et Ph

(ag)
EtO 2C

Br
O

Org. Lett. 2003, 5, 3139

N
Me

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

CO2 Me
Ph
N

CO2 Me

CO2 Me
a

NH2

HN

N
H

N
Me

N
H

N
H

CO 2Me
Ph
N

Ph

CO2 Me

O
CH2 Ph

d
N
H
Me

CO2 Me

(a) PhCHO , MeOH ; NaBH4 (b) (MeO)2 CHCH 2CH2 CO2 Me , TFA
(d) NaH , MeOH/toluene , 110C; AcOH/HCl , reflux

(c) NaH , MeI , DMF

see Tetrahedron Lett., 2000, 41, 6299

(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).

H
O

NH2 CO2 t-Bu

H
O
H
O
MeO

d
N

HN

e
N

O
(b) LiAlH4

H
O

(a) NaOMe , MeOH

(d)

H
O

(c) ClCO2 Me , NEt3

HN

H
H

O
(d) POCl3 , 90C

N
(e) LiAlH 4 , THF

All reagents in this sequence are taken from Org. Lett. 2002, 4, 1063.

magnesium cuprate (8.7.A.vi) gave the alkylated ketone.

Conjugate alkylation with the

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.

10

Organic Synthesis Solutions Manual

H
H O

H
H
H O

OH

O
d

(a) i-PrMgCl , CuI , ether (b) 1. LDA , THF-HMPA; allyl bromide 2. NaH , THF; MeI
(c) FVP , 500C (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.

a
O

b
O

O
f

O
O

g
O

TfO
O

h
O

H
H
OH
OH
(a) (TMSOCH2 )2 , 0.1 TMSOTf , CH2 Cl2 , 78C (b) 1. (TMSOCH 2) 2 , CH2 Cl2 , 78C 2. aq NaHCO3
(c) 1. LDA , THF , 78C 2. PhNTf2 . 78C
rt (d) CH2 =CHSnBu3 , Pd(PPh3 )4 , CuCl , LiCl, DMSO, 60C
(e) CH 2=C(Me)CHO , EtAlCl2 , CH2 Cl2 , 95C (f) 1. Dibal , ether , 0C 2. Na 2SO4 10 H2 O
(g) p-TsOH , H2 O , acetone, reflux (h) NaOMe , MeOH; H3 O+
H
CHO

H
OH

(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

O
N

11

O
N

CO2 Et

N
O

CO 2Et
O
c

O
O

O
(a) KOt-Bu , toluene; CaCl2 , DMSO
(d) Zn , AcOH , 100C

O
(b) Pd+2 Cu+ 2 , O2 . HCl , aq DMF

(c) KOt-Bu , t-BuOH

(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.

MeO

CH2 PPh3 Cl

CHO

BuLi
OMe

OMe
c

OMe
O

OMe

OMe

OMe
OH

OMe
f
see Tetrahedron: Asymmetry,
2000, 11, 781

(a) H2 , 10% Pd-C , EtOH

(b) BF 3 OEt

(c) acetyl chloride , AlCl3

(d) MeLi

(e) p-TsOH , PhH

(f) H 2 , 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.

12

Organic Synthesis Solutions Manual

MeO
Ar

OH

MeO

Ar

OMe

O
OH
b

MeO

OMe
MeO

MeO
d

OH

Ar

MeO

OMe

Me
N
OMe Me

NHAc

Ar

OMe

f
Ar

NH 2

Ar

OMe

OTs

Ar

OMe

MeO

OMeOMOM
Ar =
Me

(a) 5% Ti(Oi-Pr) 4 , 6% D-DIPT , TBHP , CH2 Cl2 , 20C (b) TsCl , NEt3 , DMAP , CH2 Cl2
(c) LiAlH4 , ether (d) phthalimide , DEAD , PPh3 , THF (e) 40% aq MeNH 2 , EtOH
(f) AcCl , NEt3 , CH 2Cl2 (g) POCl3 , 2,4,6-collidine, MeCN