F 4679

M.Sc. DEGREE (CSS) EXAMINATION, JANUARY 2017

Third Semester
Branch Ill-Chemistry
AN3CIO/CH3CIO-ORGANIC SYNTHESIS
(Common to M.Sc. Analytical Chemistry and Chemistry)
Time: 3 Hours Maximum Weight: 30
Scheme of Valuation
Section A

Answer any ten questions. Each question carries a weight of 1.

4 points - Grade A; 3 points - Grade B; 2 points - Grade C; 1 point - Grade D; None - Grade E

1. What is Bergman cyclisation? What is its use? What is its special advantage over usual
cyclisation reactions?

(Statement or equation – 2 points + Use – 1 point + Advantage – 1 point)

The Bergman cyclization allows the construction of substituted arenes through the
thermal or photochemical cycloaromatization of enediynes in the presence of a H• donor
such as 1,4-cyclohexadiene.

The cyclization is induced thermally or photochemically. Most cyclizations have a high

activation energy barrier and therefore temperatures around 200 °C are needed for the
cycloaromatization. The Bergman Cyclization forms a 1,4-benzenediyl diradical - a
highly reactive species, that reacts with a H• donor to give the corresponding arenes.

Page 1 of 63
 In contrast to the Bergman Cyclization, the Myers-Saito Cyclization of allenyl enynes
exhibits a much lower activation temperature while following a similar pathway:

Use - Examples

Page 2 of 63
 Special advantage of Bergman cyclisation

In the mid to late 1980s, it became clear that an emerging series of naturally occurring
antibiotics, including calicheamicin, esperamicin, and dynemicin, all
operated via Bergman cyclization to a p-benzyne derivative, followed by H atom
abstraction, especially from DNA. As a consequence of the antibiotics becoming
cycloaromatized, the cell under chemical attack suffered DNA cleavage, ultimately
leading to cell death. Therefore, the Bergman cyclisation is at the heart of the chemistry
of enediynes and is primarily responsible for their biological activities.

2. Explain the terms biogenesis, biosynthesis and biomimetic synthesis.

(Biogenesis -1, Biosynthesis – 1 and Biominetic synthesis – 2 points)

Biogenesis
Biogeneis is used as a term to describe the chemical reactions that take place in living
organisms. Biogenesis is also defined as the development of life from preexisting life. The
first step in biogenesis is the identification of the organ in which the synthetic process
occurs. The other steps are the confirmation of the chemical mechanism of the enzymes
associated with the process and the correlation of the synthesis with the general
metabolism of the living organism.

Biosynthesis
In biosynthesis, simple compounds are modified, converted into other compounds, or
joined together to form macromolecules. This process often consists of metabolic
pathways. The prerequisite elements for biosynthesis include: precursor compounds,
chemical energy (e.g. ATP), and catalytic enzymes which may require coenzymes
(e.g.NADH, NADPH)

Biomimetic synthesis
An important alternative to the disconnection approach in which the retrosynthetic plan is
biased to follow the known biosynthetic pathway for a particular target. It aims to
synthesize a target molecule through a series of reactions designed to parallel the proposed
biosynthesis. The intermediates of biomimetic synthesis are closely related to those that
occur during biosynthesis in its natural source.

3. Name three common carbonyl protecting groups used in peptide synthesis.

(Three names with structure – full credit, Names only – half credit)

R O
Me

Methyl ester

Page 3 of 63
 O

R O

Benzyl ester

R O

tert-butyl ester

4. What are the important uses of: (a) LiAlH4 (b) DMSO
(a) LiAlH4 - Uses (any one type) – Statement or general equation - 1 point
Any one synthetic application - 1 point
Lithium aluminium hydride (LiAlH4 or LAH) is a very powerful reducing agent and
reduces most of the commonly encountered organic functional groups. It has widespread
use for the reduction of carbonyl compounds. Aldehydes, ketones, epoxides, carboxylic
acids and their derivatives can all be reduced smoothly to the corresponding alcohols and
lactones to diols under mild conditions. It reduces amides, nitriles and aliphatic nitro
compounds to amines and aromatic nitro compounds, azoxy compounds and nitroso
compounds to azo compounds. It reduces disulphides and sulphoxyl chlorides to thiols and
alkyl halides to hydrocarbons. As a general rule, carbon-carbon double and triple bonds
are not affected by the reagent. Therefore, it is very useful for the preparation of
unsaturated alcohols from unsaturated aldehydes, ketones, acids, esters etc.

Applications
OH
CHO
LiAlH4
H3C O N H3C O N
CH2 CH2
H3C CH3 THF, 0 oC H3C CH3
O O

H3C H3C
LiAlH4

THF, heat
H2N COOH H2N
OH

Page 4 of 63
 Br Br
O HO
(i) LiAlH4
OCH2OCH3 OCH2OCH3
H +
(ii) H3O
OMe OMe

COOH
OH
(i) LiAlH4, ether
CH3 CH3
H2C (ii) H3O+ H2C
CH3 CH3
CH3 CH3

CN NH2

(i) LiAlH4

(ii) Hydrolysis
N N
H H

HO
(i) LiAlH4, THF

(ii) Reflux
NO 2 Me NO 2

(i) LiAlH4, ether

reflux, 30 min
Ph NO2 Ph N N Ph
+
(ii) H3O

CH2 OPMB
LiAlH4, THF CH2 OPMB
Br
H3C
r.t. H3C CH3

(PMB = p-methoxybenzyl)

O
O OH

OH
OH (i) LiAlH4, THF OH

(ii) H3O+

HO HO

Page 5 of 63
 H3C OH
O
(i) LiAlH4, THF OH
OH
(ii) H2O
H3C
H3C

CH3 CH3 CH3 CH3

H3C CH3 H3C CH3
CHO LiAlH4 CH2OH

CH3 CH3
Retinal 1 Retinol 1

H 3C CH3 CH3 H 3C CH3 CH3

CH3 CH3
CHO LiAlH4 CH 2OH

CH3 CH3

Retinal 2 Retinol 2
CH3 O CH3 OH

H H
LiAlH4
H H H H
HO HO
Estrone Estradiol

(b) DMSO - Uses (any one type) – Statement or general equation - 1 point
Any one synthetic application - 1 point
1. Swern Oxidation

The oxidation of primary and secondary alcohols to the corresponding aldehydes and ketones
using dimethyl sulfoxide (DMSO) and oxalyl chloride, (COCl)2 in dichloromethane
(CH2Cl2), and then quenching with a tertiary amine (e.g. Et3N) is called Swern oxidation.

DMSO, (COCl)2 O
OH
CH2Cl2, -780C
R1 R2
R1 R2 then Et3N

Applications

Et3SiO OH OH DMSO, (COCl)2 Et3SiO O

CHO
0
CH2Cl2, Et3N, -78 C
H C4H9 H C4H9

Page 6 of 63
 t
OSiPh2But BuPh2SiO

OOCBut O OOCBut O O O N
O OH N DMSO, (CF3CO)2O
O O
CH2Cl2, -780C
OSiPh2But OSiPh2But

OH Me Me O Me Me
S S
S Swern oxidation S
Me Me OH Me Me O

OH O
C11H23 C6H13 C11H23 C6H13
DMSO, (COCl)2
then Et3N
OSiMe2But OSiMe2But
(89%)

OMe
OMe
DMSO, (COCl)2 O
HO N3
N3 then Et3N OTBDPS
OTBDPS N
N

2. Moffatt Oxidation (Pfitzner-Moffatt Oxidation)

The oxidation of alcohols to aldehydes or ketones using dimethyl sulphoxide (DMSO) and
dicyclohexylcarbodiimide (DCC) in the presence of an acid catalyst is known as the Moffatt
oxidation.

OH O
DMSO, DCC
R1 R2 HX R1 R2

Applications

H
O2N DMSO, DCC O2N
O
OH H3PO4
p-Nitrobenzyl alcohol p-Nitrobenzaldehyde

Page 7 of 63
 O
O
Me
Me HN
HN
O N
O N OHC
HO O DMSO, DCC O
H3PO4, 250C

OCOMe
OCOMe

H H
N N
O O
AcO DCC, DMSO AcO

I CF3COO I
N
HO COOMe H COOMe
O

OH Me Me CHO
AcO N=C=N AcO
O Me Me O
AcO AcO
AcO DMSO, + CF3COO AcO
O N O
H

N Ph Ph COOEt N Ph Ph COOEt
O DMSO, EDC O
N F N F
HN N HN N
H F H F
O OH O O
Cbz Cbz

OH 1) DCC, DMSO γ α
β O
Pyridine-TFA
N H
O r.t; 19 h N
H O
O 2) RhCl3, EtOH, PhH H
O
reflux, 17 h
(+)-Paspalicine

5. Describe Jacobsen epoxidation. What are its applications?

Jacobsen epoxidation – Statement or general equation – 2 points

Any two examples/applications – 2 points

Page 8 of 63
The conversion of simple alkenes to the corresponding epoxide with asymmetric induction
using sodium hypochlorite in the presence of manganese-salen
manganese salen catalyst, where salen =
bis(salicylidene)ethylenediamine, is known as Jacobsen asymmetric epoxidation.

O
Mn-salen catalyst
R R
NaOCl, CH2Cl2
Examples
O
Mn-salen catalyst
(i)
COOMe NaOCl, CH2Cl2 Ph
Ph COOMe

O
(ii) Mn-salen, mCPBA-NMO
CH2Cl2, -780C

Styrene Styrene oxide

salen = bis(salicylidene)ethylenediamine Jacobsen catalyst (I)

salen catalyst I is called the Jacobsen catalyst, [N,N’-bis(3,5-di-tert-

The manganese-salen [N,N’
butylsalicylidene)-1,2-cyclohexane
cyclohexane-diamine]manganese(III)] chloride.

Applications

1)
(CH2)3--COOMe

Jacobsen catalyst O

OCOCH2OPh NaOCl, 4-PPNO OCOCH2OPh

(CH2)3--COOMe
pH 11.3

Page 9 of 63
 2)

C2 F 5
N O
C2 F 5 O C 2F 5
Jacobsen cat. OH
2-Piperidone
NaOCl,CH2Cl2
O Isoquinoline-N-oxide O t-BuOK O

3)

O O
Jacobsen catalyst, 8 O
N N
MeO 4-phenylpyridine-N-oxide MeO 7

NaOCl (aq.), CH2Cl2

MeO r.t., 2.5 h MeO

6. What are oxetanes? How they are produced photochemically?

(Correct description and structure – 1 points -Photochemical method with mechanism

– 3 points)

Oxetanes are 1,3 propylene oxides or oxa-cyclobutanes.

Photocycloaddition of ketones and aldehydes with alkenes can result in formation of four
membered cyclic esters (oxetanes), and is often refered to as Paterno – Buchii reaction.The
Paterno – Buchii reactions normally occurs by reaction of the triplet state of the carbonyl
compound with the ground state of the alkene. Typical examples, which show the marked
variation in the yields of products are the addition of benzophenone to propylene and
isobutylene.

H3C
hν
Ph2C O + H3C CH2 H
O
Ph Ph

CH3 H3C H3C CH3

hν
Ph2C O + H3C CH2 H3C
+
O O
Ph Ph Ph Ph
9 parts 1 parts
Mechanism

Page 10 of 63
 The ring is formed in two stages. The excited carbonyl compound (triplet) first adds
through its oxygen atom to the alkene, so as to give mainly the more stable of the two
possible diradicals. A spin inversion then occurs and the second bond is formed. The
reaction is not stereospecific, because the time lag before the final spin inversion is more
than enough for rotation to occur about single bonds.

hν O
PhHC O +
Ph H
Examples

hν
Ph2C O + O Ph

Ph

7. Give one example each for Demjanov ring expansion and ring contraction.

(Statement or general equation – 2 point, mechanism – 2 points)

Demyanov / Demjanov rearrangement. Deamination of primary amines by diazotization

to give rearranged alcohols. In the case of alicyclic amines, ring enlargement or
contraction occurs.

Mechanism
H+
N O O O
HO O N N
-H2O

Page 11 of 63
 O O O
N N -HNO2 H+

NH2 N N O N N OH
H
H
- H2O - N2 O - H+ OH
H
N N OH2 N N

Examples

NH2 NaNO2 Ph
H3C N
HOAc
H3C N + H3C N
Ph OH Ph

NaNO2 , - 0 - 4 oC

H2SO4 / H2O HO

H2N

8. Suggest suitable reagents for the following conversions:

CH3
O CH H3C
3

(i)
CH3 O

O O
O
H3C
(ii) H3C OH

CH3

Page 12 of 63
Wrong questions (the structures of the substrate and product given do not match) – Give full credit
(4 points - grade A) if attempted.

9. Predict the products of the following reactions:

(i) CrO 3

H
(ii) O N CH3 CH3COOOH
(III)
Mn

Question (ii) is cancelled (out of syllabus). Give full credit (4 points - Grade A) if the structure of the
product of (i) is given correctly.

(i) Anthraquinone.

10. What is DIBAL-H? What is the special advantage in using DIBAL-H over LiAlH4?

DiBAL-H reagent – Statement and structure - 2 points

Advantage over LiAlH4 - 1 point

Any one example/application - 1 point

Diisobutylaluminium hydride (DIBAL-H) is a very useful and widely used reducing

agent.

H
Al
DIBAL-H

Advantage

The reagent is milder and less reactive than LiAlH4, partly due to steric hindrance.This
reagent has great utility in the synthesis of aldehydes from the acid derivatives like acyl
chlorides (RCOCl), esters (RCOOR’) and nitriles (RCN). All of these derivatives are
easily reduced to alcohols. But, by working with this reagent at low temperature
conditions (-78 0C), acid chlorides, esters and nitriles are reduced to aldehydes.

Page 13 of 63
 Examples

H3CO H3CO
DIBAL-H
N N
H3CO H3CO
Toluene, -60 oC

C2H5 C2H5
CH2COOC2H5 CH2CHO
(From the total synthesis of the alkaloid emetine by Szanty et al.)

H3C H3C
COOC2H5 DIBAL-H CHO
OCH2SCH3 -90 oC OCH2SCH3

(From the total synthesis of (+)-colletodiol by Keck et al.)

OSiMe 2SiO DIBAL-H OSiMe 2SiO

t-BuMe 2SiO COOEt t-BuMe 2SiO CHO

Toluene, -60 oC

(From the Dias and Meira synthesis of a fragment of callystatin A)

H3C H3C
DIBAL-H
NC OHC
CH2 CH2

OMe CN OMe CHO

MeO MeO
DIBAL-H
CH3 CH3
CH3 CH3
NO2 NO2
(From Andrus and co-workers synthesis of (+)- geldanamycin)

11. What are the advantages of osmium tetroxide compared to KMnO4 in hydroxylation of
alkenes? What are the disadvantages?

Advantages (any two) - 2 points

Disadvantages (any two) - 2 points

Page 14 of 63
Advantages
1) OsO4 is much more compatible with other functional groups than KMnO4
2) It is soluble in a wide variety of solvents.

Disadvantages
1. The OsO4 reagent is expensive.
2. It is highly toxic and result in damage to the respiratory tract and temporary damage to the
eyes.

12. Explain the following reactions suing suitable examples:

(a) Tebbe olefination (b) Noyori reaction

(a) Tebbe reaction – Statement or general equation - 1 point

Any one example - 1 point

Transformation of a carbonyl compound to the corresponding exo-olefin using Tebbe

reagent (Cp2TiCH2.AlClMe2) is known as Tebbe olefination reaction.
O CH2 H2C
+ Cp 2Ti Al(CH 3)2 + CpTi=O + ClAl(CH 3)2
1 THF 1
R R Cl R R

1)
H H
O
O O Cp2TiCH2.AlClMe2 O O

EtOOCHN THF, r.t. EtOOCHN

2) TBSO OTBS OBn

O OPMB Cp2TiCH2.AlClMe2
PMBO O
THF, Py, 00C 230C

TBSO OTBS OBn

OPMB

PMBO O

Me
O
3) Tebbe reagent

Me Me Me Me
(16%)

Page 15 of 63
 O
Tebbe reagent, Toluene
4) COOEt COOEt
THF, 00C to rt, 30 min.
(67%)

Tebbe reagent
5) O
0 - 200C

Camphor (70%)

O
MeO
Tebbe reagent, Toluene
MeO Br
6) 0 0
Br THF, -40 C 0C rt MeO
MeO
(93%)

H H
Tebbe reagent
7)
THF, CH2Cl2 O
O O
O
(69%)

TBSO OBn OTBS TBSO OBn OTBS

Tebbe reagent
8) CHO
OHC
Toluene, THF
O OBn OTBS O OBn OTBS
TBS TBS
(86%)

9) Tebbe reagent
0
O THF, DMAP, -40 C O O
1 O 2 1
R OR R CH OR2
O 2

(71%)

(b) Noyori reaction – Statement or general equation - 1 point

Any one example - 1 point

The asymmetric reduction of carbonyl group via hydrogenation catalysed by BINAP-Ru(II)

complex is known as Noyori asymmetric hydrogenation reaction.

Page 16 of 63
 OH O O O OH O
H2 H2
1 1 1
R OR (S) -BINAP-Ru(II) R OR (R) -BINAP-Ru(II) R OR

Rh(I) and Ru(II) complexes of the enantiomers of BINAP, 21- bis (diphenylphosphino)
-1,1’-binaphthyl, are remarkably effective in various kinds of asymmetric catalysis.

Examples

1)
OH
O H2, (R)-BINAP-Ru(II)
COOBut COOBut
0
100 atm., 40 C
(97%, 99% ee)
O O
2)
OH
O
H2, (R)-BINAP-Ru (II) OH
OH
N N
Hydroxyacetone (R) -1,2-Propanediol N O
(Acetol) CH3
Levofloxacin

3) O O

OCH3 OH O
H2, (R)-BINAP-Ru (II)
NHCOC6H5 OCH3

(+/-) Methyl-2-(benzamidomethyl)- NHCOC6H5

3-oxobutanoate
(2S, 3R) - Methyl -2-
(benzamidomethyl)-3-
hydroxybutanoate
OH (99% ee)
H H

N SR
O
COOH

Carbapenems

4) O H2, (R)-BINAP-Ru (II) OH

Br 100 atm, rt Br
(92% ee)

Page 17 of 63
 O O
5) O O O -
H2, (R)-BINAP Ru(II) O OH O

OMe 0 OMe
MeOH, 70 C, 24 h H H 8
H H 8

(90% ee)

O O OH O
6) H2, (S)-BINAP-Ru(II)

OMe EtOH, rt C5H11 OMe

C5H11
(98% ee)

O O OH O
7) (R)-BINAP-RuCl2
RO RO
OMe H2, MeOH OMe
0
R = PMB 23 C, 72 h (81%, 95% ee)

13. What is DDQ? Explain its use in the synthesis of aromatic compounds using suitable
examples.

DDQ - Statement and structure - 2 points

Synthesis of aromatic compounds (2 examples/applications) - 2 points

DDQ is Dichlorodicyanoquinone (2,3-Dichloro-5,6-dicyano-1,4-benzoquinone). It is a

powerful dehydrogenating agent.

O
NC Cl

NC Cl
O

DDQ

Quinones are generally used for dehydrogenation and are reduced to the corresponding
hydroquinones or quinols. One important quinone often used for aromatization is DDQ. DDQ
is very reactive and may be used in cases where the substrate is difficult to dehydrogenate.

Applications

DDQ is an oxidizing agent useful for dehydrogenations; particularly those resulting in

aromatization.

Some important applications of DDQ are given below:

Aromatisation

Page 18 of 63
 DDQ, C6H6
reflux
Tetralin Naphthalene

DDQ, C6H6
reflux
Acenaphthene Acenaphthylene

CH3 CH3 CH3

CH3
DDQ, C6H6
reflux
(78%)

CN CN
Et Et

Et Et
NH HN DDQ, MeCN-ether N
CN NH
CN
220C, 30 min.
NH HN N HN
Et Et
Et Et
Et Et
Et Et
2) Preparation of salts containing stable aromatic cations

Ph Ph
DDQ, HClO4
Ph Ph ClO4
AcOH
Ph Ph
Triphenyl cyclopropenyl perchlorate

DDQ, HClO4
ClO4
AcOH

Tropylium perchlorate

Page 19 of 63
3) Useful reagent in steroid chemistry
O
O
AcO DDQ
Dioxan
HO
O Equilin
(a female sex hormone)

Section B

Answer any five questions. Each question carries a weight of 2.

7 or 8 points - Grade A; 5 or 6 points - Grade B; 3 or 4 points - Grade C;

1 or 2 points - Grade D; None - Grade E

14. Give three different methods for synthesising four membered carbocyclic compounds.

(Any three correct methods and their mechanisms – give full credit. The first two
methods may be given 3 points each and the third method 2 points)

(i) The Paterno – Buchii reactions normally occurs by reaction of the triplet state of the
carbonyl compound with the ground state of the alkene. Typical examples, which show the
marked variation in the yields of products, are the addition of benzophenone to propylene
and isobutylene.
H3C
hν
Ph2C O + H3C CH2 H
O
Ph Ph

CH3 H3C H3C CH3

hν
Ph2C O + H3C CH2 H3C
+
O O
Ph Ph Ph Ph
9 parts 1 parts

Give mechanism.

Page 20 of 63
 (ii) With enones and olefins

Give mechanism.

(iii) Reactions of ketene

Give mechanism.

15. Explain with examples:

(a) Baylis-Hillman reaction
(b) Nef reaction
(c) Glaser coupling
(d) Buchwald-Hartwig reaction

(a) Baylis-Hillman reaction

Statement or general equation – 1 point
Mechanism OR any one example/application - 1 point

In the presence of a Lewis base (tertiary amines such as 1,4-diazabicyclo [2.2.2] octane
(DABCO) or trialkylphosphines such as tributylphosphine), conjugated carbonyl compounds
(ketones, esters, thioesters and amides) add to aldehydes via the α–carbon to give α–alkenyl
β–hydroxy esters or amides. This sequence is called the Baylis – Hillman reaction.

N OH O
O O
N
+ R1 R R1
R H (DABCO)

Page 21 of 63
Mechanism

O O
O O H O
R1 R
R H 1 R1
R H
N
protonation
N
N
N
DABCO N
N

OH O OH O
H H N
R
R1
R R1 +
elimination N
Product DABCO
N

Applications

1)

CHO HO
COOMe
COOMe
DABCO
MeOH, 5 days
OTBDPS OTBDPS

PhCHO
2)
N DABCO
N Ph
O N O
O N O OH
Ph
Ph

OH
3) CHO CN CN
Me3N
+ H2O
O2N O2N

Page 22 of 63
 OH
4) O O O
Me
Me Me quinidine (cat.)
+ H 8
Me 8
CH2Cl2

OH

CHO COOMe COOMe

5) DABCO
+ ultrasound
O O
O O

O OH
O
O
OMe DABCO
6) H + MeOH, rt,8h
OMe
Cl Cl

OEt DABCO O O O
7) O O + dioxane:water (1:1)
OEt
O
CHO 24 h
HO
(72%, de 80%)

8) H OH
CHO
C
CH2 CH COOMe COOMe
PBu3, 2 days C
acrylate ester
CH2

(b) Nef reaction

Statement or general equation – 1 point

Mechanism OR any one example/application - 1 point

Primary or secondary aliphatic nitrocompounds (nitroalkanes) can be hydrolyzed,

respectively, to aldehydes or ketones by treatment of their conjugate bases with sulphuric
acid. This is called the Nef reaction or Nef carbonyl synthesis. Nitroalkanes are first
converted to their sodium salts and then hydrolyzed with sulphuric acid to give aldehydes
or ketones and nitrous oxide.

Page 23 of 63
 O O
O O
N N H2SO4 O
base + H2O + N2O
R R1
1
R H R1 R R

Nitrocompound Conjugate base Aldehyde

or Ketone
Mechanism

O O HO
O O O OH OH
N N N
N :Base H
H

R R1 R R1 R1
R R1 H R
I Nitrocompound II Conjugated base III Aci form of IV
nitrocompound
of nitrocompound

HO O: O
O N H
H2 O N H N
H
H H2 O R R1
1
R R1 R R OH HNO
OH OH
V VI VII

OH O
2HNO H2O + N2O
R 1
R H R1
R
VIII IX

Applications

1) 10% NaOH
1)
O
NO2 2) Conc. HCl
(40%)

Page 24 of 63
 Me3Si Me3Si

2) KF
THF
O
NO2
(64%)

3) O O
1) NaOH, EtOH, 00C, 30 min
2) 3M HCl, 200C, 12 h
NO2 O

(68%)

NO2
HO HO O
1) 2M NaOH, MeOH
4)
2) ice cooled KMnO4
H H
(Basic permanganate reagent is used) (45%)

NO2
OMOM O
5) t-BuO OMOM
O O
OPMB , H2 O
Me Me OPMB

(72%)

COOEt
COOEt
1) aq. NaOH
2) H2SO4
6) OH
3) NaOH, HOAc OH
NO2
N
N
H2N N NH2
N N
H2N H

Page 25 of 63
 O
NaOH CH3CH2CH2CH=N H2SO4 CH3CH2CH2CHO
7) CH CH CH CH NO
3 2 2 2 2 O
Nitrobutane Butanal

8)
TiCl3 (M cM urry
+
NO 2 O modification)
NO2

NO 2 O
9) 1) LDA

CH 3 2) MoO 5 , Py CH 3
HMPT
(85% )

10)
1) NaOH
2) 2N HCl

NO 2 O O

NO2 O
11) SiO 2 . N aO H

(99% )

(c) Glaser coupling

Statement or general equation – 1 point

Mechanism OR any one example/application - 1 point

The oxidative homo-coupling of terminal alkynes using copper catalyst in the presence of
oxygen to give diynes is known as Glaser coupling.

CuCl, O2
2R H R R
NR3

Page 26 of 63
Mechanism

NR3 O2
R H R Cu
CuCl
homolytic cleavage

R R R R
dimerisation
Applications

1) Cu, NH4Cl
O2 HO OH
HO

2) CuCl2, NaOAc
H
CO2(l)

3)
Cu2Cl2, O2
Me2C C CH Me2C C C C C CMe2
pyridine, MeOH
OH OH OH

C C C C
4) Cu2Cl2, O2
HC C(CH2)4 C CH
NH4Cl, 550C
C C C C

5)
Cu(OAc)2
p MeOOC C6H4 OH2C C CH (p MeOOC C6H4 OH2C C C )2
MeCN, Ar

6) CuCl, O2
2 H
NH4OH, EtOH
Phenyl acetylene 1,4-Diphenyl-1,3-butadiyne
(90%)

Page 27 of 63
 MeOH2CO O
7)
MeOH2CO O
NH O OSi(i-Pr)3
NH O
OSi(i-Pr)3
O
i N Cu(OAc)2, THF
PrO OMe O
N
i OMe
OMe Cl 0
CuI, Py, 45 C PrO
O Br OMe Cl
O
Br
t
BuMe2SiO
t
BuMe2SiO

(d) Buchwald-Hartwig reaction

Statement or general equation – 1 point

Mechanism OR any one example/application - 1 point

The direct palladium catalysed coupling of aryl halides or triflates with amines (or alcohols)
in the presence of stoichiometric amount of base leading to C-N (and C-O) bond formation is
called the Buchwald-Hartwig reaction or amination. The Pd(0) catalyst is usually
complexed with chelating phosphine type ligands such as BINAP or DPPF. The strong bases
used for the reaction include sodium tertiary butoxide and lithium bis(trimethylsilyl)amide,
also known as lithium hexamethyl disilazide (LHMDS), LiN(SiMe3)2.

H Pd(0) R
N Ar-N
Ar-X + R R1 NaOBut, tol, R1

Coupling of aryl halides with alkoxides gives aryl ethers (C-O bond formation).

Page 28 of 63
Mechanism
R
Ar-N Ar-X
R1 L Pd L
[=Pd(0)]
reductive
elimination oxidative
addition

R1 L
N X
R L Pd
Pd Ar L
Ar L
R
R1 H-N
t-BuOH + NaX R N X R1
Pd
base takes out HX Ar H
and 2 Ls come back + 2L
to fill the space t-BuONa

The C-O bond formation follows a similar mechanistic pathway.

Applications

0.5mol% Pd2(dba)3
1mol% ligand
1) O Cl + HN O
NaOBut, Tol.
O N O

1000C, 24 h
(92%)
i-Bu
i-Bu P N i-Bu
N N
ligand =
N

(Verkade's Superbase)

Page 29 of 63
2) NH2 COOMe
COOMe
H
I Pd(OAc)2, DPE-Phos N
+ Cs2CO3, Tol., 950C OCF3
OCF3 (95%)
PPh2 PPh2
O
DPE-Phos =

Ar
3) OBn
N
N NH
N
N OTBDMS
Br Pd2(dba)3, BINAP HN N N
HN N N OTBDMS
NaOBut, ArNH2 DMT O
O OTBDMS
DMT
OTBDMS
(nucleotide of guanine)
O

where Ar =

(83%)
(72%)

O
O
O N Pd(OAc)2, DPPF
4) 1 2
X N Br + R NHR
0
O N R
1

NaOBu-t, 80 C, 14 h X N N 2
R
X = N, CH2

O O-Bu-t O O-Bu-t

Pd(OAc) 2, XPhos
5) + NaOBu-t, toluene, rt, 4d
MeO NH2 MeO NH N Cl
Cl N Cl

O O
NH2 NEt2
NEt2 Pd2(dba)3/BINAP
6)
+
Br NaOBut/PhMe, 90-1000C N Ph
H

Page 30 of 63
 H
Br (DPPF) PdCl2 N
7) NH2Ph Ph
+ THF/1000C, 3 h
Ph Ph

16. Give the total synthesis of Luciferin.

(Correct scheme – give full credit)

The chemical structure of D-luciferin (1), isolated from firefly tails, was proposed in 1961
and later confirmed by synthesis. In this procedure, p-anisidine (4) is the starting material
that, through intermediates (5) and (6), is transformed into the thioacid (7), in turn cyclized
to 6- methoxybenzothiazole-2-carboxylic acid (8). From this benzothiazole derivative, 2-
cyano-6- hydroxybenzothiazole (12) is prepared in four steps. Compound 12 is the key
intermediate for the synthesis of 1, that can be obtained almost quantitatively by reaction
with D-cysteine, in situ produced by reduction of D-cystine.

Reagents and conditions: (a) ethyl oxalate, 180 °C, 5 min, 58%; (b) P2S5, reflux, 40 min;
(c) NaOH, 0 °C then HCl; (d) K3Fe(CN)6/OH- , <10 °C, 15 min; (76% crude , no isolation
in steps b-d); (e) CH2N2, 0 °C, 15 min, 40%; (f) anhydrous NH3/MeOH, heat, 30 min,
100%; (g) POCl3, reflux, 15 min, 56%; (h) PyHCl, 200 °C, 1 h, 62%; (i) D-cysteine (in
situ from D-cystine/liquid NH3/Na, r.t., 10 min) and 12 in H2O/MeOH, r.t., 0.5 h, 94%.

The overall yield of D-luciferin (1) from p-anisidine (4) is 9% through nine steps.

Page 31 of 63
 17. Explain with suitable examples the important roles played by trimethyl silyl group in
modern organic synthesis.

(Structure of any two silyl protecting group with explanation – 2 points, Protection – 3
points, Deprotection – 3 points)

Silicon-based protecting groups for alcohols are the best because they are the most
versatile. They are removed by nucleophilic displacement with fluoride or oxygen
nucleophiles and the rate of removal depends mostly on the steric bulk of the silyl group.
The simplest is trimethylsilyl (TMS) which is also the most easily removed as it is the
least hindered – they have low stability – cleaved under acidic or basic conditions to
alcohols or attacked by some nucleophiles. Deprotection is done by HF. (Due to corrosive
nature of HF, its replaced by tetra-n-butylammonium fluoride.)

Protection

Deprotection

Replacement of the one of the methyl groups with a much more sterically
demanding tertiary butyl group gives the t-butyldimethylsilyl (TBDMS) group, which is
stable to normal handling and survives aqueous work-up or column chromatography on
silica gel. The stability to these isolation and purification conditions has made TBDMS
(sometimes over-abbreviated to TBS) a very popular choice for organic synthesis.
TBDMS is introduced by a substitution reaction on the corresponding silyl chloride with
imidazole in DMF. Yields are usually virtually quantitative and the conditions are mild.
Primary alcohols are protected in the presence of secondary alcohols. Removal relies on
the strong affinity of fluoride for silicon and is usually very efficient and selective.
However, a protecting group is useful only if it can be introduced and removed in high
yield without affecting the rest of the molecule and if it can survive a wide range of
conditions in the course of the synthesis. The extreme steric bulk of the t-
butyldiphenylsilyl (TBDPS) group makes it useful for selective protection of unhindered
primary alcohols in the presence of secondary alcohols.
The most stable common silyl protecting group (triisopropylsilyl or TIPS) has three
branched alkyl substituents to protect the central silicon from attack by nucleophiles which
would lead to cleavage. All three hindered silyl groups (TBDMS, TBDPS, and TIPS) have
excellent stability but can still be removed with fluoride.
Page 32 of 63
18. Write down the important intermediates formed in the biosynthesis of proteins.

(Any correct explanation with the steps of biosynthesis of proteins – give full credit)

The mechanism of duplicating the entire nucleotide sequence in DNA replication

is used by nature and by chemists to obtain partial copies of the genetic code for various
purposes. In nature, the most important application is the assembly of RNA, called
transcription, which transcribes the parts of the DNA that contain the information (the
genes) necessary to synthesize proteins in the cell. The process by which this transcribed
information is decoded and used to construct proteins is called translation. The three key
players in protein synthesis are the “DNA transcript” messenger RNA (mRNA), the
“delivery unit” for the special amino acids to be connected by peptide bonds, transfer
RNA (tRNA), and the catalyst that enables amide bond formation—the ribosome.

Figure 1 Simplified picture of m-RNA synthesis from partially unwound DNA

Protein synthesis starts with mRNA, a transcript of a piece of a single strand of

partly unwound DNA (Figure 1). Its chain is much shorter than that of DNA, and it does
not stay bound to the DNA but breaks away as its synthesis is finished. The mRNA is the
template responsible for the correct sequencing of the amino acid units in proteins. Each
sequence of three bases, called a codon, specialises a particular amino acid. Simple
permutation of this three-base code with a total of four bases gives 43 = 64 possible
distinct sequences.
Each tRNA is specifically designed to carry one of the 20 amino acids for
delivery to the mRNA in the course of protein build-up. The amino acid sequence
encoded in mRNA is read codon by codon by a complementary three-base sequence on
tRNA, called an anticodon. At this stage, catalytic ribosomes (very large enzymes)
containing their own RNA facilitate peptide-bond formation (Figure 2). As the
polypeptide chain grows longer, it begins to develop its characteristic secondary and
tertiary structure (a helix, pleated sheets, etc.), helped by enzymes that form the
necessary disulfide bridges.

Page 33 of 63
 Figure 2 Representation of the biosynthesis of the tripeptide Gly-Ala-Asn

19. Give the mechanism of the following reactions:

(a) Sharpless asymmetric epoxidation

(b) Woodward modification of Prevost reaction

(c) Selenium dioxide oxidation

a) Sharpless asymmetric epoxidation

Statement or general equation – 1 point

Mechanism – 2 points

The enantioselective epoxidation of allylic alcohols using t-butyl hydroperoxide,

tetraisopropoxy titanium IV [Ti(Oi-Pr)4] and optically pure (+)- or (-)- diethyl tartrate (DET)
is known as Sharpless asymmetric epoxidation (SAE).

R1 R1 R3
R3
t-BuOOH, Ti(Oi-Pr)4
O
OH L-(+)-diethyl tartrate OH
2
R R2

R1 R3
R1 R3
t-BuOOH, Ti(Oi-Pr)4
O
OH D-(-)-diethyl tartrate OH
2
R R2

Page 34 of 63
Mechanism
'top face'
D-(-)-Diethyltartrate
[O]
1 3
R R

R1 O

2 OH
R2 R3 R
1 3
R R
OH O
2 OH
R
[O]
L-(+)-Diethyl tartrate
'bottom face'

OEt
COOEt
O
i-PrO O O Oi-Pr
Ti Ti
i-PrO O O Oi-Pr
O
EtOOC
OEt

The active catalyst

OH O O
O i-Pr O
Ti Ti Ti
O i-Pr t-Bu-O-OH O
O
O t-Bu
The active catalyst t-Bu

O O O HO
O O O
O
Ti Ti Ti
O O
O
t-Bu t-Bu
t-Bu

(b) Woodward modification of Prevost reaction

Statement or general equation – 1 point

Mechanism – 2 points

Page 35 of 63
 In presence of water (usually in presence of acetic acid containing water), iodine and
silver acetate converts alkenes into diacetyl derivatives of the cis-diol, which on
saponification yields the cis–diol. This is called Woodward modification of the Prevost
reaction.
For example, cyclohexene on treatment with iodine and silver acetate in moist acetic acid, the
diacetate of cis-1,2-dihydroxy cyclohexane is formed, which on saponification yields the cis-
diol.

O CH3 OH
I2, CH3COOAg
Saponification
O
CH3COOH
O CH3 OH
O
cis-1,2-Dihydroxy
cyclohexane
Mechanism
-
OCOCH3

+ -
+ I I + AgOCOCH3
- AgI
I
+

Iodonium ion

O CH3 O O
+
O CH3 CH3
I O
.. O
+
-
Iodoacetate CH3COO
Oxonium salt

O O O CH3
route b CH3
CH3

O -H+ O
O H O
OH
H2O
Oxonium salt

O CH3 OH
AgOCOCH3 Saponify
3
O
O CH3 OH
O
cis-1,2-Dihydroxy
cyclohexane
(c) Selenium dioxide oxidation

Statement or general equation – 1 point

Mechanism – 1 point

Page 36 of 63
Selenium dioxide is a common reagent for allylic oxidation.. This reagent is used to
selectively oxidize an alkyl fragment, and it is effective for oxidation of allylic or benzylic
fragments to the corresponding allylic alcohols. In most applications, carbonyl derivatives are
oxidized to 1,2-dicarbonyl compounds and allylic hydrocarbons to alcohol or esters.

Eg.

CH3 CH3 CH3 CH3

SeO2, t-BuOOH
HO
H3C OAc CH2Cl2, 25 oC OAc

Mechanism

H ene
O H O
R reaction R Se O R Se
Se
O O O
H
allyl selenic acid

[2,3]-sigmatropic OSeOH H 2O OH
reaction
R R
Se(II) ester allylic alcohol

20. Explain the following metal-mediated couplings:

(a) Ullman reaction

(b) Nozaki-Hiyamacoupling

(c) Suzuki coupling

(d) Sonogashira coupling

(a) Ullman reaction

Statement or general equation – 1 point

Mechanism OR any two examples/applications - 1 point

The homocoupling of aryl halides in the presence of Cu (or Ni or Pd) to afford biaryls is
known as the Ullmann coupling reaction or Ullmann biaryl synthesis.

Cu
2 Ar-X Ar-Ar + CuX2

Page 37 of 63
 For example, when iodobenzene is heated with copper powder, biphenyl is formed in 80%
yield.

Cu
2 I + CuI2

Mechanism

Cu Cu(I)I
I + Cu(II)I
single electron Cu(I)I SET
transfer

I
CuI2 +

Applications

1)
MeOOC
COOMe COOMe
Cu, DMF OMe
Br MeO
MeO
OMe
OMe MeO

N N N
2) 1) Cu,
I
N 2) KCN, NH3 N N

OMe OMe
OMe
3) I
2 Cu
NO2
, DMF NO2 NO2
OMe OMe
OMe

Page 38 of 63
 4) Pd/C, Zn
Ar-X Ar Ar
H2O, CO2(l)

X = I, Br, Cl
Me

F3C CF3
Me
(87%) (95%)

Me Me
5) O
But OMe Cu(0)
N
2 Pyridine
Br OMe Me Me
OMe O
t
Bu OMe
N
OMe
MeO OMe
OMe
O
MeO
N
Me Me
But

6)
NO2
NO2
Cu powder, DMF N
N
N Cl 100-1050C, 4 hr
O2 N

O
N
S O
7) Cu
N

I I NMP, rt

Page 39 of 63
 OEt
OMe O O
I Cu-bronze
8) OEt MeO OMe
0 MeO OMe
MeO 210-220 C
O

OEt

b) Nozaki-Hiyama coupling

Statement or general equation – 1 point

Mechanism OR any two examples/applications - 1 point

The chromium/nickel bimetallic catalyst-promoted redox addition of allyl or vinyl halides or

triflates to aldehydes forming alcohols is known as the Nozaki-Hiyama-Kishi (NHK)
reaction.

OH
CrCl2, NiCl2
R1-CHO R1
R X + DMSO
R

Examples

CrCl2, NiCl2
i) Br + OHC
COOMe
THF

OH

COOMe

O O
CrCl2, NiCl2
ii) + PhCHO
DMF Ph
I
OH

Page 40 of 63
Mechanism

2 Cr(III) R-X
Ni(0)

oxidative
reduction addition

2 Cr(II) R-Ni(II)-X
Ni (II)

transmetalation
R-Cr(III)-X Cr(III)

OCr(III)X OH
hydrolysis
R1-CHO R1 R1
R R
nucleophilic
addition
In a modification, the amount of chromium (toxic) needed was minimized by making it
catalytic by a coupled reaction with manganese.

Mn(0) 2 Cr(III)

redox redox

Mn(II) 2 Cr(II)
Applications

1)

CrCl2, cat. NiCl2 Ph

C10H21 OTf + PhCHO 0
C10H21
DMF, 25 C
OH

Page 41 of 63
 2)
OBn
BnO OBn
OBn O
OBn OBn O
OH
CrCl2, NiCl2 O
O DMSO, r.t.,
H
O oxygen free
O OBn
O
BnO
I

+ 3 eqv. OTBDPS
OBn (mixture of enantiomers)
BnO

OTBDPS

OTHP
3) AcO + I OTBDPS
CHO

OTHP
10 eqv. CrCl2, cat. NiCl2
AcO
DMSO, 250C, 12 hr OTBDPS
OH

4) O OH
OHC O
OTf O 4 eqv. CrCl2, 0.008 eqv. NiCl2 O
+ O DMF, r.t. 15 hr O

5)
OTBDPS OTBDPS
Me Me

CrCl2, NiCl2
O O
DMF
CHO Br
OH
Me Me Me Me

Page 42 of 63
 I
6) CrCl2, NiCl2 N
N
CHO DMF OH

O O
7)
OHC
O CrCl2, NiCl2 O

I DMF HO
OTBS OTBS
OTBS OTBS

(c) Suzuki coupling

Statement or general equation – 1 point

Mechanism OR any two examples/applications - 1 point

The palladium-catalysed cross-coupling reaction of organo boron compounds usually aryl or

vinyl boronic acids or organo boranes with organic electrophiles like aryl or vinyl halides,
triflates etc. in the presence of a base (transmetalation is reluctant to occur without the
activating effect of a base) to give biaryls or alkadienes is known as Suzuki coupling or
Suzuki-Miyaura coupling.

PdL4
Ar - X + Ar1B(OH)2 Ar Ar1
NaOH

L2Pd(0)
R X + R1 B(R2)2 R R1
NaOR3

(where, X = I >> Br > OTf > Cl)

Example

O Pd(PPh3)4 Bu
B Bu Ph
Ph-I + NaOH or NaOEt
O
(catechol boronic ester)

Page 43 of 63
Mechanism
L L
Pd
L L
-2L activation
Ar-Ar1
L-Pd-L Ar-X
reductive [= Pd(0)] oxidative
elimination addition

L X
Pd
Ar L
Ar1 L
Pd NaOR activation
Ar L by base
NaX
L OR
Pd
Ar L

L Ar1-B(OH)2
cis-trans ligand Ar1
Pd
isomerisetion Ar L transmetalation
RO-B(OH)2

Applications

COOEt O
1)
+ B OTBS Pd(PPh3)4
OTf O
C5H11 K3PO4, dioxane
850C

COOEt
OTBS

C5H11

Me Me
HO Pd2(dba)3, P(t-Bu)3
2) B MeO
MeO Cl + HO KF, THF, 700C

(dba = dibenzylidene acetone)

Page 44 of 63
 HO Pd(OAc)2, PCy3 t-Bu
3) t-Bu OTf + HO B
KF, THF, rt
Me Me

Me
OH I
4) Me Pd (Pt-Bu3)2
B + MeOOC
CsF
MeOOC OH

HO OH
OMe
B

I Pd(OAc)2, P(o-Tol)3
5) + K2CO3, acetone (aq)
N I N

SO2Ph OMe SO2Ph OMe

BnO
6)
TBDMSO B2H6 TBDMSO
O OBn
O
TBDMS I B- (CH2)6 TBDMS
3 (CH2)6-OBn

Pd(dppf)2Cl2, Cs2CO3
OTBDMS OTBDMS

I
COOMe O
7) B
N COOMe
+ O

COOEt

COOMe
Pd(OAc)2, Ph3P
K2CO3, THF, MeOH N COOMe
0
70 C, 15 h COOEt

Page 45 of 63
 I B(OH)2
8)
N Pd(Ph3P)4, Na2CO3
+
I N
N I
TBS
SEM

I
N

I
N
N

SEM TBS

9)

B(OH)2
O O

TfO OTf
+ Pd(PPh3)4, K3PO4

OMOM KBr, dioxane, 1000C

MOMO
OTBS

O O

TBSO OTBS

MOMO OMOM
(TBS/TBDMS = t-Butyldimethylsilyl)
10)

Ts
Ts
I N Br
N
+ Pd(PPh3)4, MeOH N

Br N OMe Br
PhH, Na2CO3, H2O N
(HO)2B
800C, 72 h
Br N OMe

Page 46 of 63
11)
OMe
Pd-C,
O I O
B(OH)2 Na2CO3, 450C
+ THPO O DMF/H2O, 1 h THPO O
MeO

(THP = Tetrahydropyranyl)

12)
CH3
ROOC
NHCOOBu-t CH3 t-BuOOCHN
B(OH)2
ROOC Pd(PPh3)4
OMe
+ K2CO3
TfO OMe
OMe
OMe
13)
OH NO2 Cl
NO2
B Cl Pd(PPh3)4
OH

Cl
+ t-BuOH, H2O
0
K2CO3, t-BuOK, 160 C

14)
CN CN
HO
Suzuki
Cl + B
coupling
HO

(d) Sonogashira coupling

Statement or general equation – 1 point

Mechanism OR any two examples/applications - 1 point

The palladium catalysed and Cu(I) co-catalyzed coupling of aryl or vinyl halides (or triflates)
with terminal alkynes in the presence of CuI and a base, often i-Pr2NEt or Na2CO3, at room
temperature (or on mild heating) to afford disubstituted alkynes is termed Sonogashira
coupling.
PdCl2.(PPh3)2
R1 X+ H 2
R R1 R2
CuI, Et3N, r.t.

[X = I, OTf, Br, Cl; iodides work best]

Page 47 of 63
Examples

PdCl2.(PPh3)2
i) X + H R
R
CuI, Et3N, DMF
microwave

Pd.(PPh3)2Cl2
ii) I + H SiMe3 SiMe3
0
CuI, Et2NH, 30 C
NH2 NH2

Mechanism

R= aryl, vinyl or pyridinyl

R R2 R1-X
L-Pd(0)-L X= halogen or OTf

reductive oxidative addition

elimination
X
2
L
R Pd
R1 cycle A
Pd R 1 L
L L

cis-trans
isomerization
R2 transmetalation
L
Pd
R 1 L
Cu R2
+
Cu X
R3NHX
cycle B
R3N
H R 2

H R2

Cu+X

Page 48 of 63
Applications

1)
OTf
TMS Ph(p-OMe)
O Cl O
O
O 5% Pd(PPh3)4
+
OTBS CuI, DMF, i-Pr2NEt
MeO OH
OTBDPS
OMOM
II
I
Ph(p-OMe)
O
O
OH OTBS
O
O
TMS
MeO Cl

OTBDPS
III OMOM

PdCl2(PPh3)2
2) + CuI, TEA, 600C
N

Br N Br
CHO OHC CHO
(60%)

N N
PhI, Pd(PPh3)2Cl2, CuI
3) H Ph
N N Et3N, DMSO, 1000C, 3 h N N
H H

I
PdCl2.(Ph3P)2
4) +
N COOEt CuI, Et3N, 600C N COOEt
H H

Page 49 of 63
5)
Br PdCl2.(Ph3P)2,CuI
+ SiMe3 Br
N Br Et3N, r.t.
N
SiMe3

PdCl2(PhCN)2, P(t-Bu)3 R1
6) Br + H R1
CuI, i-PrNH, dioxane
R
R

7) O Me H
Me OH
Pd(C3H5)Cl, CuI

+ K2CO3, DMF, 1000C O

OH
I

Pd(Ph3)P4
8) O
TBDPS +
N CuI, pyrrolidine
I

OTBDPS
N

OPMP

O O
OPMP
OTBS
O O
OTf
OH
OTBS
O O O TMS
9) O TMS OH
Cl OTBDPS Cl OTBDPS
Pd(Ph3)4, CuI
MeO MeO
i-PrNEt2 : DMF (1:1)
OMOM OMOM

Page 50 of 63
10)
OTHP H SiMe3
Cl
+ H Pd(PPh3)4
Pd(PPh3)4, CuI, BuNH2
Cl OTHP CuI, BuNH2 Cl
(72%)

OTHP
THP = Tetrahydropyranyl,
O
SiMe3 (90%)
IV

21. What is hydroboration? Give the mechanism of the reaction. Show how the reaction is
useful in the synthesis of large variety of compounds.

Hydroboration – Statement or general equation – 2 points

Characteristics of the reaction (any two) – 2 points
Mechanism – 2 points
Applications (any two type) – 2 points

The process of addition of borane to alkenes and alkynes to form alkyl- and alkenyl- boranes
respectively is called hydroboration.

C C + H B H C C B

Normally, reaction of borane with alkenes does not stop after the addition of one BH3
molecule, because the resulting RBH2 adds to another molecule of alkene to give R2BH,
which in turn adds to a third alkene molecule; thus the final product is trialkylborane, R3B.

RCH=CH2
RCH=CH2 + BH 3 RCH2CH2BH2 (RC2CH2)2BH
Monoalkyl borane Dialkyl borane

RCH=CH2
(RC2CH2)3B
Trialkyl borane

However with hindered alkenes, the reaction stops either in the mono- or dialkylation stage.
These hindered boranes are less reactive and are more selective.
The major characteristics of the hydroboration reaction are the following:

1. The reaction is essentially instantaneous and quantitative with addition of H and B to the π-
bond of an alkene

Page 51 of 63
 ) 3B OH
[O]
BH3
+

2. The reaction proceeds by a cis addition of the H-B bond, probably via a four-centre
transition state. (HB = hydroboration)

H H
HB B [O] OH

3. The boron adds regioselectively at the less sterically hindered position. In other words, the
addition proceeds in an anti-Markovnikov manner.

R HB R [O] R
)3B OH

4. The boron adds stereoselectively to the less sterically hindered face of the alkene. Reaction
with norbornene, for example, gave 99.6 % of the exo-borane with 0.4 % of the endo-borane.

HB
+
B

Norbornene 99.6 % B
0.4 %

5. Hydroboration proceeds without skeletal rearrangement, at normal temperature, as in the

hydroboration of α-pinene.

HB B [O] OH

α-Pinene

6. In ether solvents, most functional groups can tolerate hydroboration, if the stoichiometry of
the reagent is controlled.

CH2=CHCH2COOR B CH2CH2CH2COOR

CH2=CHCH2CN B CH2CH2CH2CN

7. The organoborane product can be oxidized, eliminated, rearranged, protonated and

aminated, leading to a large number of functional group transformations.

Page 52 of 63
Mechanism
The addition of B-H unit to the double bond involves a simple four centre transition state. Boron
being electron deficient begins to add to the double bonded carbon. In accordance with the
Markownikoff’s rule, the positive charge develops on that carbon of the double bond which is best
able to support it. Intramolecular hydride shift then completes the reaction.

H
H
H B δ− δ+
H B H
H
CH3 CH CH2 CH3 CH CH2 CH3CH2CH2BH2
δ+ δ−
Alkylborane

Because of the one-step four-centre process, hydroboration is cis-addition; the hydrogen and
boron become attached to the same side of the double bond. As there is no free carbocation,
rearrangement is not to be expected.

Uses

The alkylboranes obtained as a result of hydroboration are useful intermediates in the

preparation of a wide variety of organic compounds. The presence of other groups such as
OR, OH, NH2, SMe, COOR, X etc. will not affect the reaction.

(i) Oxidation to alcohols

An important use of hydroboration reaction is that the alkylboranes can be converted to
alcohols on oxidation with H2O2/NaOH. Thus this method, known as hdroboration-
oxidation, serves as an indirect method of hydration of alkenes in an anti-Markownikoff
manner.

The advantage of this process is that no rearranged product is formed as in the case of the
acid catalysed hydration of alkenes. The mechanism of oxidation involves initial attack of
HOO- ion to boron, followed by migration of alkyl group from boron to oxygen. Resulting
borate ester liberates alcohol on hydrolysis.

H2O2 + HO- HOO- + H2O

R
HOO- 2 HOO-
R3B R B R2B-OR B(OR)3
- HO-
R O
OH
HO-

OH
-
2HO
(RO)2B-OH RO B
B(OH)3 + 2RO -
- RO- RO OR

Page 53 of 63
Examples

1)

CH3 BH THF CH3 CH3

3 H2 O2
THF NaOH
2 BH OH

2)

H OTIPS H OTIPS
H 1. BH3.DMS H
THF, rt, 3h N
N N
N
H H 2. NaOH, H2O2, 2 h H H
H 19
H OH
19 20 H 20

3)

MOMO 1. 9-BBN MOMO

MOMO 0 OH
OH PdCl2 0 C to rt
THF N N
NH 2. NaOH, H2O2 Boc H
Boc
Boc

(ii) Oxidation to aldehydes and ketones

Direct oxidation of primary trialkylboranes to aldehydes and of secondary trialkylboranes to

ketones, without isolation of the alcohol, is possible with pyridinium chlorocromate (PCC) or
aqueous chromic acid (formed from Na2Cr2O7 and H2SO4). For example, 1-octene was
converted directly to octanal using disiamylborane, followed by oxidation with PCC

i) (C5H11)2BH
CHO
ii) PCC, CH2Cl2

1) BH3 O

2) Na2Cr2O 7/H2SO4

(iii) Alkylation of α-halo compounds

Trialkylboranes react rapidly and in highly yields with α-halo ketones, α-halo esters, α-halo
nitriles and α-halo sulphonyl derivatives in the a base to give, respectively, alkylated ketones,
esters, nitriles and sulphonyl derivatives.

Page 54 of 63
 t-Bu
-
O
1 1
R R
Br t-Bu
+ R3B
0
R
O THF, 0 C O

(iv) Michael-type addition to activated double bonds

Alkylboranes undergo rapid conjugate addition to the double bonds of α,β-unsaturated

carbonyl compounds (like acrolein, methyl vinyl ketone etc) to give Michael-type products
by addition of R and H.

1 0
R 1) THF, 25 C R 1
R 1
+ R3B
2) H2O
(R = H, Me)
O O

(v) Coupling of boranes

Alkylboranes can be coupled by treatment with silver nitrate and base to yield alkanes. Since
alkylboranes are easily prepared from alkenes, this is essentially a way of coupling and
reducing alkenes. Alkenes can be hydroborylated and coupled in the same flask. This method
provides a useful method for the formation of carbon-carbon bond.

B
+ B
AgNO3
1
1
R R
R R NaOH

Alkylboranes undergo many other reactions as well. They react with CO to give alcohols
and ketones. They can be reduced with carboxylic acids. They can be isomerized, or
converted to amines, halides or carboxylic acids.

Section C

Answer any two questions. Each question carries a weight of 5.

16 to 20 points - Grade A; 11 to 15 points - Grade B; 6 to 10 points - Grade C;

1 to 5 points - Grade D; None - Grade E

22. What is solid phase peptide synthesis? What is the special advantage of it compared to solution
phase peptide synthesis? How the following peptide can be synthesised by SPPS: Cys-Glu-Ala-Gly

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Solid Phase peptide synthesis (SPPS) – Statement – 4 points

Basic principles (General outline) – 6 points

Advantages (any three with details) – 6 points

Synthesis of tetrapeptide (outline with correct structures

of amino acids – 4 points
Solid Phase Peptide Synthesis (SPPS)

Solid Phase Peptide Synthesis (SPPS) is an unconventional method of peptide

synthesis introduced by R.B. Merrifield, in which an amino acid or a peptide is bound
chemically to an insoluble, solid polymer support (resin) and the then the chain is built up,
one amino acid residue at a time, at the free end. When the desired peptide has been
synthesised, it is liberated from the solid support. SPPS has greatly enhanced the convenience
and speed of laboratory operations, particularly since the development of automatic
instruments which carry out the sequential operations for extended periods of time without
human attention or intervention.

Basic principles of Merrifield’s SPPS

The principle of Merrifield’s solid-phase of peptides is illustrated in the figure given

below. The most commonly employed resin support is chloromethylated, 1% crosslinked co
(polystyrene-divinylbenzene), now known as ‘Merrifield resin’. The resin thus provides
‘benzyl chloride’ groups through which the ‘first’ amino acid becomes attached as the benzyl
ester.

The ‘first’ amino acid, which is to be the C—terminal end of the peptide, is protected
at its amino group by, e.g. t-butyloxycarbonyl (Boc) group, and is heated with the resin in the
presence of triethylamine in a suitable solvent (step i).

The second step (ii) involves the deprotection of the amino group (NH2 group) under
conditions that do not cleave the resin-amino acid ester bond, e.g. the Boc group is removed
by hydrolysis with trifluoroacetic acid in CH2Cl2. In the third step (iii), a second N-
protected amino acid is coupled to the amino group of the polymer-bound amino acid using
dicyclohexylcarbodiimide (DCC) or some other coupling agent. The N-deblocking (ii) and
coupling (iii) steps are repeated until the desired sequence is formed.

Finally, the resin—peptide bond is cleaved by a suitable acid-catalysed cleavage

reaction (using HF), which results in simultaneous N-deblocking and of most other side chain
functionalities (step iv).

Since only the final peptide is obtained by cleavage from the polymer, the purity of
the final product depends on the coupling efficiency of each step. This efficiency should be
quantitative, or at least better than 99%, for the synthesis of long chains.

Page 56 of 63
 Fig. An outline of solid phase peptide synthesis

1
P CH2Cl + HOOC-CHR -NH-Boc

Et 3N
(i) [Attachment]
EtOAc

1
P CH2OCOCHR NH-Boc

CF3COOH
(ii) [N-deblocking]
CH2Cl2

1
P CH2OCOCHR -NH2

2
HOOC-CHR -NH-Boc
(iii) [Coupling]
DCC

1 2
P CH2OCOCHR NHCOCHR NH-Boc

Repeat steps (ii) and (iii) n times

1 2 n
P CH2OCOCHR NHCOCHR NH- - - - - - -COCHR NH-Boc

(iv) Acidolysis with HF

[Final cleavage of resin-peptide & deblocking

1 2 n
P CH2F + HOOCCHR NHCOCHR NH- - - - - - - - COCHR NH2

Advantages of SPPS

1) Easy separation of the polymer (including all chains attached to it) from all other reagents,
because it is insoluble in the solvents used.

2) Time saving due to avoiding of purification of the intermediates.

3) Automation of peptide synthesis.

4) High yields by minimizing mechanical losses of the product.

Page 57 of 63
Synthesis of the peptide Cys-Glu-Ala-Gly by SPPS – give the outline with correct
structures of the amino acids.

Structures of the amino acids:

Cys is Cysteine, HSCH2CH(NH2)COOH

Glu is Glutamic acid, HOOCCH2CH2CH(NH2)COOH

Ala is Alanine, CH3CH(NH2)COOH

Gly is Glycine, CH2(NH2)COOH

CH2CH2COOH
CH2SH CH3

H2NCHCONHCHCONHCHCONHCH2COOH

Cys-Glu-Ala-Gly
23. Give the biomimetic synthesis of Sparteine.

(Correct reaction scheme with relevant reagents – 10 points)

Van Taneler’s synthesis of sparteine (6) begins with piperidine. In this example, the
synthetic equivalent of (3) in the bis(iminium) ketone (2), generated from amino-ketone
(1) by treatment with mercuric salt. Generation of the synthetic equivalent (2) lead to (4)
and then (5) via sequential Mannich reaction. Wolf-Kishner reduction of (5) gave (6).
O

H3C CH3 Hg(OAc)

2
HCHO, AcOH
N N N
H
O
1

+ + CHO
N N NH NH
OHC
O O
2 3

O
+
N
+
N N
N

O
4

Page 58 of 63
 H H
H H
N N2H4 N

O N
N
H H
H H

5 6
Sparteine

(b) Write down the Enantioselective synthesis of Longifolene.

(Correct reaction scheme with relevant reagents – 10 points)

24. How the following heterocyclics synthesised?

(Give total five points for two methods in each case – 3 points for the first method and
2 points for the second method)

Page 59 of 63
 a. Imidazole

(i) Condensation of a 1,2-Diamine with a Carboxylic Acid

Condensation of an ortho-bisaniline with a carboxylic acid derivative is the best method
for preparation of benzimidazoles. Carboxylic acids, acid chlorides, and anhydrides32
have been utilized successfully for this transformation.

(ii) Condensation of an Amidine with a Halocarbonyl Derivative

A good method for preparation of imidazoles is the reaction of an amidine with a
carbonyl compound containing a leaving group at the alpha-position.

b. Thiazole
(i) Condensation of Thioamides with Haloketones
A practical method for the preparation of a thiazole is the condensation of a
thioacetamide with a haloketone, which generally proceeds in high yield.

(ii) Condensation of Carboxylic Acid Derivatives with 2-Aminothiols

The most common method for preparation of benzothiazoles is the reaction of 2-
aminothiols with carboxylic acid derivatives.

c. Oxazole

(i) Cyclodehydration
The cyclodehydration of an acylated a-aminoketone is the most common method for
the preparation of oxazoles. The reagent of choice for this preparation is POCl3,
although many other dehydrating agents have been utilized.

Page 60 of 63
 (ii) Dipolar Cycloaddition
The dipolar cycloaddition of an isonitrile, most commonly tosylmethyl isocyanide
(TosMIC) with an aldehyde is a popular method for the preparation of 5-substituted
oxazoles.

d. Thiophene

(i) Cyclodehydration of 1,4-Dicarbonyl Derivatives

Thiophenes and benzothiophenes can be obtained by cyclodehydration of 1,4-
dicarbonyl compounds in the presence of a sulfur source.

(ii) Knoevenagel Condensation

Thiophenes and benzothiophenes can be obtained by Knoevenagel condensation of an
enolate with a carbonyl compound under acidic or basic conditions

25. Write down the important steps in the biosynthesis of cholesterol starting from
acetyl coenzyme-A.

(Total 20 points – give full credit)

Cholesterol – synthesised from 2C building blocks – acetyl-CoA – acetoacetyl-CoA

thiolase interconverts acetyl-CoA and acetoacetyl-CoA which are then condensed by
3 – hydroxyl – 3 – methyl glutarate (HMG)-GA synthase to HMG-CoA.

Page 61 of 63
 HMG-CoA reductase catalyses the redn of HMG-CoA to Mevalonate – uses 2
NaDPH its metabolised to Farnesyl – diphosphate by a series of enzymes -
mevalonatekinase phosphorylates 5–OH group of Mevalonic acid. The pdt
Mevalonate5 – P is again phosphorylated to Mevalonate–5–PP – decarboxylated and
dehydrated by mevalonatepp decarboxylase to form isopentyl – PP which is in
equilibrium with dimethylallyl – PP.

Farnesyl PP synthase converts 2 moles of isopentyl – PP and dimethyl allyl – PP to

Farnesyl – PP. The enzyme squalene synthase condenses two molecules of Farnesyl –
PP to presqualene PP intermediate which is the reduced to squalene. By the action of
squaleneepoxidase and Oxidosqualenecyclase, squalene is converted to Lanosterol.
By a series of oxidations.

Page 62 of 63
 Reduction and demethylation converts lanosterol to cholesterol.

--------------------------------------------------------------------------------------------------------------------------------------
End

Page 63 of 63