Chapter 16 1

CHAPTER 16

1. Friedel-Crafts alkylation is not a useful synthetic method for the synthesis of primary arenes
such as 1-phenylhexane. Explain why not.
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. Briefly explain the regioselectivity for this reaction.

2. There are two activating substituents on the aromatic ring, an OH and a CH2R. The oxygen has
electron pairs that can stabilize the arenium ion 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. Therefore, acylation occurs at C2.

OH H OH
O
Ac Ac
H H Ac
see J. Org. Chem. 2000, 65, 2574
Versus
H
COOH COOH COOH

NH2 NH2 NH2

2 Organic Synthesis Solutions Manual

3. Provide a mechanistic rationale for the following transformation:

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 (in red). 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 (in green).

OMe OMe OMe OMe

+ H2O
TsOH

aq acetone
H H H H

OH2
OMe O Me O Me OMe
OMe OMe OMe

- MeOH - H+

H H H

OH OH O
OHMe H H
OMe OMe

OH OH
- H+

H
 Chapter 16 3

4. Offer a mechanistic rationale for the following transformation:

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 oxocarbenium ion, which loses a proton
to give the bromomethyl-ketone product.

OH OH Br OH Br Me Me
CH2 Br+ - H+

Me Me Wagner- Me
Me Me Meerwein Me Br O
see Tetrahedron: Asymmetry 2000, 11, 3059

5. Give a mechanistic rationale for the following transformation:

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.

OMe OMe OMe OMe OMe OMe

Silica gel H+

Cl

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

4 Organic Synthesis Solutions Manual

6. Give a mechanistic rationale for this transformation:

6. The mechanism is taken from J. Am. Chem. Soc. 2003, 125, 1498. Note that the bond that migrates in
the carbocation intermediate is aligned anti rather than syn.

AlMe3
Me3Al Me3Al OH
O OH OH
O OH Me3Al
O O
CH2Cl2

OSi(i-Pr)3 OSi(i-Pr)3 OSi(i-Pr)3

OSi(i-Pr)3 OMe OMe OMe
OMe

Me3Al-O OH
HO O

MeO
MeO OSi(i-Pr)3
OSi(i-Pr)3

7. Give the complete mechanism for the following transformation.

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.

MeO MeO MeO MeO

H+
HO HO
O H O N Me
H H
N Me N Me N Me

MeO MeO MeO MeO

MeO MeO H+ MeO

H+ - H2O
H2O CHO CHO
HO HO - MeCl HO
NHMe Tautomerisation

Cl- MeHN
MeHN
Me-O O-Me OH
 Chapter 16 5

8. What are the mechanistic implications of the following experiment? Of what possible value is
this experiment to synthesis if the R—NH2 → R—OH transformation is planned?
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.

OH2

H3C NH2 OH2

H3C N2 H3C H3C

CH3 CH3 CH3 CH3

CH3 = 14 CH3

9. Give the complete mechanism for the following transformation.

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

OBn OBn Boc OBn Boc

NHBoc OBn
NHBoc
N H N
O
OH2
-H2O
H+ - H+
OH HO + H+

C6H13 C6H13 C6H13

C6H13

N N N N H
OBn Boc OBn OBn Boc –O OBn Boc
Boc 2CH
HCO2
HCO2 HCO2 HCO2 C6H13
C6H13 C6H13 C6H13
6 Organic Synthesis Solutions Manual

10. Explain the fact that Wolff-Kishner reduction of A gave B but Clemmensen reduction of A gave
C.
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.

O OH OH
OH

N N N
N
O Zn H
H
•
see J. Am. Chem. Soc. 1949, 71, 3089
N N N
H H

11. Give a reasonable mechanism for the following transformation.

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.
OTs OTs
OTs OTs OTs

BF3•OEt2 , CH2Cl2 Ph Ph - BF3

Ph
Ph Ph
O 0 °C O
F3B O O
BF3 BF3 O
see J. Org. Chem. 2003, 68, 5917

12. Provide a mechanism for the following transformation:

12. The mechanism proposed for this transformation is taken from Org. Lett. 2003, 5, 333. Markovnikov
addition to the iminium ion generates a new carbocation. Attack by the aromatic ring gives the
phenonium ion intermediate, and formation of the ketone unit regenerates the aromatic ring to complete
the rearrangement.

Br Br Br
H H
Br
H
N N H
N HCOOH N
- H+ O
1 2
toluene 2 1
2
reflux
HO
HO 3
3 HO 1 3
 Chapter 16 7

13. For each of the following, give the major product. Show the correct stereochemistry where
appropriate.
13.
OMOM
HO
H O
(a) N Ph (b) (c) O Me
O
OH OTBS
O
O O OMOM
J. Am. Chem. Soc. 2002, 124, 6552 J. Org. Chem. 2002, 67, 6690 J. Am. Chem. Soc. 2003, 125, 1843
CO2Et
AcHN
CO2H
MeO O
N Bn
MsO
(d) (e) (f)

MeO N
Me OH
CO2Me
Org. Lett. 2002, 4, 3339 J. Am. Chem. Soc. 2003, 125, 2400 J. Am. Chem. Soc. 2003, 125, 13486
OH
O

(g) Br (h) (i)

H
see J. Am. Chem. Soc. 1961, 83, 3998
especially pp 4002-4003 Org. Lett. 2003, 5, 3931 Chem. Eur. J. 2002, 8, 853
OAc
Me
Me H
H BzO OAc
O O

(j) H O O (k) O (l) O

OAc

H NH
O
Me
OMe O O
see Org. Lett. 2000, 2, 1875 Org. Lett. 2002, 4, 1343 Eur. J. Org. Chem. 2004, 209

O O MeO
N H
N
O
(m) + (n) (o) MeO
H Et MeO2C H
MeO N
HO OH
see Tetrahedron 1993, 49, 1649 Org. Lett. 2003, 5, 749 Org. Lett. 2003, 5, 535
8 Organic Synthesis Solutions Manual

OH Me CO2H
OHC
(p) (q) (r) N•HCl
CO2Et
MeO N
H N
Me OH H
Org. Lett. 2003, 5, 4481 J. Org. Chem. 2003, 68, 6279 J. Am. Chem. Soc. 2003, 125, 4541

O CO2Et Ph
(t) EtO2C
(s) Br
N Et
O
N
N
H Me
O Org. Lett. 2003, 5, 3139 J. Org. Chem. 2002, 67, 2889

14. In each case give a complete synthesis of the target from the designated starting material. Show
all intermediate products and give all reagents.
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 (7.4). A Pictet-
Spengler cyclization using the acetal shown was followed by N-methylation. A final Dieckmann
cyclization ([Link]) closed the last ring, and heating with acetic acid/HCl gave decarboxylation to the
final product.

CO2Me CO2Me O
CO2Me CO2Me CH2Ph
H
N Ph N Ph
NH2 HN c d
a b
Ph
H
N N N N
H H H CO2Me Me CO2Me N
Me
(a) PhCHO , MeOH ; NaBH4 (b) (MeO)2CHCH2CH2CO2Me , TFA (c) NaH , MeI , DMF see Tetrahedron Lett. 2000, 41, 6299
(d) NaH , MeOH/toluene , 110 °C; AcOH/HCl , reflux
 Chapter 16 9

(c) All reagents are taken from Org. Lett. 2003, 5, 1123. Treatment of the free amine with base led to
formation of the lactam (4.2.2), which was reduced with lithium aluminum hydride to the amine (7.6.1).
Formation of the carbamate ([Link]) allowed a Pictet-Spengler cyclization (16.5.2), and reduction of the
lactam as before provided the amine (β-lycorane).

H
a b H c
O
O O
H
HN H
NH2 CO2t-Bu O HN
O O
O
H H H
O d O e H H
H H O
N N H
O O N
MeO O
O O
(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 ([Link]) gave the alkylated ketone. Sequential enolate alkylation reactions with
LDA (13.3.1) treatment to form the enolate anion, followed by addition of an alkyl halide gave the tri-
alkylated ketone. Flash vacuum pyrolysis induced the retro-Diels-Alder reaction (14.8.2), and alkylation
of the ketone with the organolithium reagent (11.6.4) generated from 4-bromo-1-butene and lithium metal
11.6.1) gave the final target.

O O O
H H O OH
H
H H H
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-bromobut-1-ene , Li , ultrasound
10 Organic Synthesis Solutions Manual

(e) 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 (6.4.4) 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.

O O O O
O
O O O O
a b c d e
O O O
O O O O O TfO
O O O

O O
O O
O O

O f O g h
O

O O
H
H H OH
H
CHO OH OH
(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. Na2SO 4•10 H2O
(g) p-TsOH , H2O , acetone, reflux (h) NaOMe , MeOH; H3O+

(f) All reagents are taken from Org. Lett. 2002, 4, 631. Sharpless asymmetric epoxidation ([Link]) gave
the epoxy-alcohol, which was converted to the tosylate, and then the tosyl group reduced to the methyl
([Link]), with concomitant reduction of the epoxide to the alcohol ([Link]). A Mitsunobu reaction
([Link]) converted the alcohol to the amine, which was acetylated ([Link]), allowing a Pictet-Spengler
cyclization (16.5.2) to the final product.

OH OH OTs
O O MeO
MeO MeO MeO
a b c
OH
Ar
Ar Ar Ar
OMe
OMe OMe OMe
MeO MeO MeO Me
d e f
NH2 NHAc N
Ar Ar Ar
OMe OMe OMe Me
OMeOMOM
(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 Ar =
(f) AcCl , NEt3 , CH2Cl2 (g) POCl3 , 2,4,6-collidine, MeCN Me