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1.1. INTRODUCTION

The functional group transformation is one of the most fundamental

and useful reactions in organic synthesis. Though the transformation of an

isolated functional group can be carried out conveniently with a number of

reagents, selective transfer of one functionality in presence of other such

groups with minimal or without damage to the sensitive portion of a

molecule in substrate is a frequent problem in organic synthesis.

Consequently, a significant effort has been undergone in developing new

methods and finding new reagents that are chemo-selective or able to

transform one functional group in a polyfunctional group molecule, leaving

the remaining ones untouched and this area of developing selective, mild

and effective reagent systems is still an area of prominent interest.

REVIEW: Reductive Functional Group Transformations Chapter 1

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To perform desired modifications to a functional group in organic

synthesis, reduction is considered as one of the significant tools in the hands

of chemists. The most widely used general methods of reduction are,

i) metal/acid reduction, ii) catalytic hydrogenation, iii) electrolytic

reduction, iv) metal hydride reduction.

Generally the methods effecting reduction may or may not lead to

hydrogenation. Reduction of organic functional groups can be categorized

into (i) addition of hydrogen to unsaturated groups as, for example in the

reduction of ketones to alcohols and (ii) addition of hydrogen across single

bonds leading to cleavage of functional groups (hydrogenolysis). Of all the

methods available for reductions, heterogeneous catalytic transfer reactions

have been relatively underutilized. This lack of popularity can be traced to

the relatively meager success of much of the earlier research, which

suggested that the technique was of only limited scope and could provide

only modest yields of products. The early pioneering work of Braude [1] was

largely ignored because of poor yields and long reaction times, but the

situation has changed considerably following the introduction of greater

catalyst loadings and different hydrogen donors [2]. Another reason for the

underutilization of transfer reductions has been the very successful

exploitation of molecular hydrogen and hydrides for reduction of organic

compounds. In view of the above said facts, the following sections of this

review on reductive functional group transformations are focused on

catalytic transfer hydrogenation (CTH) methods of reductions.

The transfer reductions carried out using hydrogen donors have some

real and potential advantages over catalytic reductions, where the

molecular hydrogen is being used. The use of hydrogen donors for reductions

makes the processes simple and environmental friendly which involves

usually just stirring of solutions. Unlike catalytic reductions, it requires no

pressure vessels and gas containers, and there by avoid the use of molecular

hydrogen of high diffusibility which can be easily ignited and lead to

substantial amount of hazards. Potentially, transfer methods could afford

enhanced selectivity in reduction. With a catalyst and molecular hydrogen,


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changes of catalyst, solvent, and temperature are possible variations in

reaction conditions but, with hydrogen donors, a new dimension is opened

up because the choice of hydrogen donor can affect the reaction through its

competitive adsorption onto the catalyst surface. Thus, rate and specificity

of reduction are amenable to control through choice of hydrogen donors.

Most transfer hydrogenation mechanisms are poorly understood and there

are a few direct comparisons of products of reactions following the use of

molecular hydrogen or a hydrogen donor. Research in these areas is needed

not only to unravel details of mechanisms, but also to provide a proper

appraisal of the advantages or disadvantages of the two methods.

According to Pauling’s definition of electronegativity [3], hydrogen,

having a value of 2.1, lies between fluoride (4.0) and many metals, which

typically have values of about 0.9-1.5. Therefore, in reactions involving its

transfer, hydrogen may appear as a proton, atom, or hydride depending on

reagents and conditions. For example, when a gaseous HCl is dissolved in

water, hydrogen is transferred as proton to water similarly the reaction of

lithium tetrahydroaluminate to a carbonyl group involves the addition of

hydride to carbon of the carbonyl and in many catalytic hydrogenations with

molecular hydrogen; atomic hydrogen is dispersed in and over the catalyst.

But, in many reductions with hydrogen donors, it is difficult to decide how

hydrogen is transferred.

1.1.1 HYDROGEN DONORS:

The low oxidation potential of the compound (donor) facilitates the

transfer of hydrogen(s) from the donor to the substrate even under mild

reaction conditions. Hence, any compound (organic or inorganic) with a low

oxidation potential can be served as a useful hydrogen donor. The choice of

donor is based on the nature of the reaction, its availability, and solubility

in the reaction medium. Alcohols, hydrazine, cyclic olefins, and

hydroaromatics have been employed as hydrogen donors for the transfer

hydrogenation of various functional groups. Formic acid and its salts occupy

a special place as hydrogen donors because, the ease of hydrogen donation


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is higher than with the donors listed above. This results from the fact that a

stable molecule such as CO2, which has a very large negative enthalpy of

formation (∆Hf, 298 ºC = 395.51 kJ/mol), is released from the hydrogen donor

during the transfer hydrogenation reaction. Simply stated, the hydrogen

donation is irreversible. This is one of the major driving forces for the high

reactivity of formates.

The common property of the useful donors is irreversible nature of

their dehydrogenated products. For instance, CO2, N2 and C6H6 are the

dehydrogenated products of ammonium formate, hydrazine and

cyclohexadiene respectively.

As previously said, the nature of the hydrogen donor influences the

selectivity of the reduction. This can be demonstrated with the reduction of

aromatic nitro compound containing halogen using palladium in conjunction

with a formate salt, where halogen being effectively removed and nitro

group reduced to amino group. While, the same catalyst coupled with

phosphinic acid as hydrogen donor reduces only nitro group without

affecting halogen [4].

Even though one can use common types of compounds as hydrogen

donors in both homo- and heterogeneous catalysis, it is more often the case

that different types of compounds are favored in the two systems. The more

active hydrogen donors for homogeneous catalysis appear to be

predominantly alcohols, hydroaromatics, cyclic ethers, and occasionally

formic and ascorbic acids whereas, for heterogeneous catalysis, the more

widely used donors tend to be hydrazine, formic acid and formates,

phosphinic acid and phosphinates, indoline, and cyclohexene. There is no

clear division between the two types, but some of the hydrogen donors,

which are active for heterogeneous catalysts, are water-soluble inorganic

salts and cannot be used with many homogeneous catalysts. Trialkylsilanes

and trialkylstannanes have proved to be good hydrogen donors in both

homo- and heterogeneous catalysis [5], where tri-n-butylstannane reduced

α,β-unsaturated aldehydes in methanol under fairly drastic conditions [6], in


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the presence of Pd(PPh3)4 and a promoter, the reduction can be achieved in

10 min at room temperature [5].

1.1.2 CATALYSTS:

The transfer hydrogenation reactions can be accomplished using both

homogeneous and heterogeneous catalysts.

Homogeneous Catalysts: The majority of the homogeneous

hydrogenation catalysts are soluble complexes of noble metals and are

equally active for transfer hydrogenations also. Literature [7] accounts the

applications of RuCl2(PPh3)3, RhCl(PPh3), PdCl2(PPh3)2 and IrCl(PPh3)3. As

most of these complexes are insoluble in water, these reactions are carried

out in nonaqueous media. Metal complexes having water-soluble ligands

(m-sulphophenylbiphenylphosphine, for example) have been designed for

reactions that demand an aqueous or a biphasic medium. The homogeneous

catalysts are often appended to an insoluble polymer to overcome the

product isolation difficulty while retaining the advantages of homogeneous

catalysts.

The catalytic activity of the transition-metal salts and complexes is

the result of a delicate balance of valence states and strengths of chemical

bonds [7]. Too strong a bond between hydrogen donor and the transition

metal results in stable compounds showing no catalytic activity. Similarly,

there is no catalytic activity if reaction between hydrogen donor and the

transition element cannot occur. Not only must the hydrogen source be

accommodated by the transition metal, but also the organic substrate must

be able to bond if transfer of hydrogen to the substrate is to occur.

Usually the operational temperatures for homogeneous catalytic

reactions are rarely low (i.e., 20-80 ºC), they require moderate to high

temperatures in the range of 100-200 ºC. Another problem associated with

homogeneous catalysts has been the difficulty of their recovery from

reaction products. Unfortunately, many of these catalysts appear to be

unstable and lose the complexed metal to the reaction medium (i.e., the


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catalyst is dissolved from its support) or the complex salt is reduced to the

metallic state.

Heterogeneous Catalysts: Most of the heterogeneous hydrogenation

catalysts are also of transition metal elements but they are used in their

zero oxidation state. Sometimes, the catalyst is used in the bulk form; this

is possible when a base metal is used, for example, Raney nickel. But, it is

not advisable to use in bulk when a costly metal like platinum is used. To

maintain the cost effectiveness, such catalysts are used in supported form

which increases the surface area as well the availability of metal atoms for

catalysis, thus more efficient the catalyst. Generally, catalyst supports

employed are activated carbon, alumina, silica, amorphous silica-alumina,

zeolites, BaSO4, and CaCO3. The crystalline size and hence dispersion of the

supported metal depends on the method of preparation and subsequent

treatments. For 10% Pd/C, the Pd crystalline size is estimated to be

3.5 - 5 nm [8].

The most widely used catalyst support for liquid phase hydrogenation

reactions is activated carbon. This can be justified by the following reasons:

(1) Activated carbon can be synthesized with high purity and possesses large

surface area (~1000 m2/g); (2) The metal support interaction is the least

among the various common catalyst carriers and thus the electronic

properties of the active material are not modified; and (3) Activated

carbon, being a good adsorbent for organic compounds, can facilitate the

reaction by aiding the migration of the adsorbate to the active sites of the

catalyst.

Even though palladium is preferred for most of the common

reactions, platinum, ruthenium, and rhodium are also useful complementary

candidates when selectivity is crucial. For instance, a ruthenium complex

can be used to selectively transfer hydrogenate the carbonyl group to a

carbinol in α,β-unsaturated carbonyl compounds [9], while Pd/C is used to

selectively reduce the C=C double bond [10]. Similarly, in halo-

nitroaromatics, Pt/C can be employed to reduce nitro groups without


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eliminating halogen functionality while Pd/C may be utilized to remove

halogens with simultaneous reduction of nitro groups to amines [11].

1.1.3 REACTION CONDITIONS:

Influence of Temperature: In homogeneous systems, at equilibrium

or under steady-state conditions, normal solution kinetics can be applied

and energies of activation and enthalpies have been determined

experimentally for several systems [12-18]. In a practical sense, increase in

temperature will lead usually to a faster overall rate of reaction, i.e., faster

reduction, but for equilibria, the change in position of equilibrium with

increasing temperature is not easy to predict. In many reductions, a linear

increase in rate of reduction with increase in temperature has been

observed [12,13,16,17,19].

Comparatively, homogeneous catalyst requires higher temperature to

transfer the hydrogen from a donor to an acceptor than heterogeneous

catalyst of the same metal. However, increasing temperature may lead to

unwanted reactions like over reduction and isomerization [20,21]. Given the

less importance to side-reactions, increase in temperature of reaction can

afford higher yields of product for a given time of reaction. Different

hydrogen donors may require different optimum temperatures. Similarly,

variation in the hydrogen acceptor will afford various optimum

temperatures for any one hydrogen donor. As mentioned above, the effect

of temperature on equilibria is unpredictable without experimental data.

Influence of Solvent: Choosing a suitable solvent is an important

factor for governing the activity of a soluble catalyst in transfer reduction.

Most soluble catalysts are either coordinated to ligands or coordinated with

solvent. Often, ligands can be displaced from a metal complex by a suitable

solvent to form new complexes. These new complexes incorporated in

solvent molecules may be more or less active than the original complex,

because binding by the solvent alters the electron density around the

central metal atom and changes its ability to effect oxidative addition.

Some metal catalysts are active in solution only after dissociation of one or


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more ligands leaves the central metal atom with less than its maximum

coordination number, thereby facilitating oxidative addition. If solvent

molecules displace the original ligands and they themselves do not

dissociate from the central metal, then all catalytic activity is lost. In

additions to these ligand-displacement mechanisms by the solvent, catalyst

activity may be reduced or destroyed completely if the solvent coordinates

to the catalyst better than the hydrogen donor or hydrogen acceptor.

Finally, the solvent should not deactivate the catalyst by destroying it, as

may happen with water.

In heterogeneous catalyst systems also, coordination of solvent to the

catalyst must be competitive with binding of hydrogen donors and

acceptors. If the coordination between solvent and catalyst is stronger than

the binding of donor or acceptor, then transfer reduction is inhibited or

stopped altogether. Hence in order to optimize the conditions for any

attempted transfer reduction, a trial of a range of solvents should be a

principal consideration

The most common solvents for these reactions are alcohols,

particularly methyl or ethyl alcohol. Dimethylformamide and

dimethylacetamide are useful for reactants that are less soluble in alcoholic

solvents. Acetic acid is very effective as a solvent medium when acidic

conditions are demanded.

The rate of mixing or stirring of reactants in heterogeneous transfer

reductions can also make the difference in reaction rate. Increased mixing

improves the contact between the catalyst and the reactants, thus results in

a beneficial effect on the reaction rate. In addition to the familiar process

parameters such as temperature and pressure, ultrasound is found to

promote the Pd-catalyzed reduction of olefins using HCOOH in alcohols [22].

1.1.4 MECHANISM OF TRANSFER HYDROGENATION:

To the date, Pd/C is the most preferred catalyst for transfer

reduction reactions and at the same time formate slats as donors. In an

attempt to know the mechanism of transfer hydrogenation, the following


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postulate is advanced to rationalize the various literature observations that

have been made.

The first step in these reactions is the chemisorption of formate salts

that may decompose into CO2 and H- ions on the metal surface. The

adsorbed hydrogen can exhibit H-, H, or H+ behavior depending on the

environment. There is some evidence that hydrogen exhibits either H- or H+

character on palladium in the liquid-phase. For example, in the case of

dehalogenation, it is most likely that the hydride-like behavior is

predominant. In the case of coupling reactions performed in the presence of

a strong base such as NaOH, the chemisorbed hydrogen on palladium may

exhibit H+ character; the abstraction of this H+ by OH- would leave two

electrons on the surface of the metal cluster. These electrons may be

responsible for the radical chemistry witnessed in the coupling reaction of

bromobenzene to biphenyls. The H-D exchange reactions also support the H+

nature of PdH- species. For example, the deuterium of PdD- can exchange

freely with H2O, alcohols, benzylic protons, organic acids, and NH4+.

1.1.5 REACTIONS INVOLVING VARIOUS FUNCTIONAL GROUPS:

A wide range of functional groups are modified by applying transfer

hydrogenation or hydorgenolysis methods. In all cases, the advantages of

transfer hydrogenation over conventional hydrogenations are obvious. The

most important functional groups reduced by CTH include alkenes, alkynes,

arenes, nitroalkanes, nitroarenes, azo compounds, aldehydes and ketones,

nitriles, azides, hydrazo compounds and imines [23]. Several important

functional groups have received little study, in particular, carboxylic acids,

their esters and their amides. All of them are frequently reduced efficiently

by hydride reagent, but are usually found not to be reduced under any of

the conditions described in this catalytic transfer hydrogenation.

Further, the application of CTH systems for reduction of aromatic

nitro compounds to corresponding amines, azoarenes to hydrazoarenes,

imines to secondary amines, synthesis of indolones and quinolones via


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reductive cyclization, and synthesis of amides of amino acids and peptides

are discussed in detail which comprise the present work of this thesis.

1.2 REDUCTION OF AROMATIC NITRO COMPOUNDS

The transfer reduction of nitro compounds dates way back to 1943 by

Davison and Hodgson [24], they used copper to catalyze the transfer

hydrogenation of nitrobenzene in the presence of HCOOH at 200 °C. More

and Furst [25] have used Raney-nickel with hydrazine hydrate to reduce 2,2'-

dinitrobiphenyl to 2,2'-diaminobipheyl, wasn’t a mono-reduction. Entwistle

and coworkers [2, 4] have used cyclohexene as a hydrogen donor and 10%

Pd-C as the catalyst for the mono-reduction of polynitrobenzenes (Table

1.1, Entry 1). They [4] also reduced nitroarenes in 75-90% yields using Pd-C

catalyst and one of phosphinic acid, sodium phosphinate, phosphorous acid

or sodium phosphite as donor. Selective mono-reduction of dinitroarenes

could not be achieved with the donors other than cyclohexene because,

with them, the rate of reduction of nitro aniline is greater than its rate of

formation from a dinitroarene. Triethylammonium formate and 5% Pd-C at

~90-100 °C was used to reduce the nitroarenes (Table 1.1, Entry 2) [11]

and have reported the formation of cyclized products with o-nitoro

phenylacetic acid and o-nitro cinnamic acid. Similar works with a

Pd/AlPO4/SiO2 catalyst has been reported [26].

Dehalogenations are common during catalytic transfer reduction and

substitution reactions may also be observed. Later on, successful attempts

made to gain greater control of these reductions by using less active

catalysts and variation of the solvent have been reported [27]. In the

presence of a 50% excess of hydrazine hydrate; a number of nitro benzenes

were reduced with Fe(III) chloride on active carbon. An indication of how

much less active Fe(III) is as a catalyst than Pd is found in the lengthy

reduction times (Table 1.1, Entry 3). However, high yields of amines were

obtained and reduction of 5-chloro-2,4-dimethoxynitrobenzene to the

corresponding aniline was effected without loss of the chloro group.


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Other formate salts such as alkali metal formates are also useful but

result in the formation of bicarbonate. Water-soluble organic nitro

compounds [e.g., disodium salt of 3,6,8,1-(HO3S)3C10H4NO2] were reduced to

the corresponding amines in aqueous HCO2H or its salts in the presence of

Pd-C [28]. Aromatic nitro compounds like nitro phenols and nitro amines

were conveniently reduced by catalytic transfer hydrogenation employing

HCOOH in the presence of palladium black by Sivanandaiah and coworkers

(Table 1.1, Entry 4) [29].

Ram and Ehrenkaufer [30] described the transfer hydrogenation of a

wide variety of both aliphatic and aromatic nitro compounds using

ammonium formate at room temperature with conversions ranging from 31%

to 98% (Table 1.1, Entry 5). Reductive cyclization of 2-nitro-β-nitrostyrene

to indole is achieved using ammonium formate and 10% Pd-C in fair yield

(60%) [31].

Lin et al. [32] have reported the system triethylammonium formate

with Pd-C catalyst for the transfer hydrogenation of nitrocoumarins to give

aminocoumarins in good yields.

Namura [33] has used the ruthenium-carbonyl complexes in presence

of small amounts of amines for selective reduction under CO/H2O conditions

to get excellent yields (Table 1.1, Entry 6). He has observed that the use

of amines enhanced the catalytic activity. Brinkman et al. [34] selectively

reduced the nitro groups using rhodium complexes in conjunction with

triethylsilane at higher temperatures (Table 1.1, Entry 7).

Upadhya et al. [35] described the chemoselective reduction of

nitroarenes using nickel stabilized zirconica (Zr0.8Ni0.2O2), propan-2-ol and

KOH under reflux condition with good yields (Table 1.1, Entry 8).

Ultrasonic promoted reactions for the reduction of nitro compounds is

reported to be of useful methods. Nagaraja et al. [36] have used

alluminium/ammonium chloride system to effect the reduction under

ultrasonic bath at 25ºC, where as the reaction takes much longer time


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(24 hrs) under conventional reflux conditions with the same system (Tabel

1.1, Entry 9). Basu et al. [37] also reported the reduction of several

aromatic nitro compounds to aromatic amines with high yields using

samarium/ ammonium chloride mediated reactions.

Benz and Prins [38] reported a kinetic model for the reduction of

4-nitrotoluene to 4-toluidine and 4-nitroaniline to p-phenylenediamine by

hydrazine hydrate in the presence of iron oxide as hydrogen-transfer

catalyst. Bae et al. [39] described the chemo-selective reduction of

nitrobenzenes to corresponding anilines with decaborane (B10H14) in the

presence of Pd-C and two drops of acetic acid at reflux temperature under

nitrogen atmosphere (Table 1.1, Entry 10).

Use of microwave heating for chemical applications has given a new

dimension to organic synthesis. This technique is widely accepted as non

conventional energy source for performing organic synthesis. Vass et al. [40]

have reported the microwave assisted reductions using iron chloride

hexahydrate and hydrazine hydrate to get fairly good yields with time range

7 to 10 mininutes (Table 1.1, Entry 11).

Mahapatra and co-workers [41-43] reported the use of various metal

incorporated molecular sieves for the CTH of nitroarene. They used cobalt

(II) (CoHMA) and trivalent iron (FeHMA) incorporated hexagonal mesoporous

aluminophosphate molecular sieves (Table 1.1, Entry 12 and 14). Further,

they observed regio- and chemoselective CTH upon using nickel containing

mesoporous silicate (NiMCM-41) molecular sieve catalyst (Tabel 1.1, Entry

13) with propan-2-ol as hydrogen donor. In extension, Selvam et al. [44]

reported the use of nickel incorporated hexagonal mesoporous

aluminophosphate molecular sieves (NiHMA) (Tabel 1.1, Entry 15). They

also used mesoporous PdMCM-41 catalyst with HCO2NH4 in MeOH as solvent

for chemoselective reductions of nitroarenes [45] (Table 1.1, Entry 16).

Ionic liquids are being used as reaction medium, which are considered

as environmentally benign and are widely used in recent years. In this

concern, Khan et al. [46] have reported zinc mediated chemoselective


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reduction of nitroarenes to amines using ammonium salts in imidazolium

ionic liquids (Table 1.1, Entry 17).

Wang et al. [47] have reported the use of nanosized activated

metallic iron powder in water at an elevated temperature of 210 °C (near

critical water) (Table 1.1, Entry 18).

Polymer supported reagents are mostly talked of, when we consider

the clean and recyclable reagents. Very recently in our laboratory, Abiraj et

al. [48 (Table 1.1, Entry 19), 49] utilized polymer supported reagents in

various functional group transformation reactions. They used polymer

supported formate as hydrogen donor to reduce nitroarenes to

corresponding amines in excellent yields. Shi et al. [50] have prepared

aromatic amines through chemoselective reduction of the corresponding

aromatic nitro compounds by using polymer supported hydrazine hydrate

over iron oxide hydroxide catalyst in propan-2-ol at reflux temperature

(Tabel 1.1, Entry 20).

In the recent past, our laboratory has produced a number of reagent

systems for the reduction of aromatic nitro compounds containing other

reducible moieties such as carbonyl, ethene, ethyne, nitrile, acid, phenol,

etc., in good yields. Some of the systems are Zn/NH2NH2 [51], HCOONH4 or

HCOOH [52], Raney-Ni/NH2NH2.HCOOH [53] or HCOONH4 or HCOOH [54],

Pd-C/HCOONH4 or HCOOH [55] and Pt-C/HCOONH4 or HCOOH [56].


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Table 1.1. Reduction of nitroarenes to arylamines.

NO2 NH2

ConditionsRR

Entry Conditions R (Yield %) Ref.

1 10% Pd/C, Cyclohexene, 10-120 min

2-NO2, 3,6-OMe (85%), 4-NO2, 3,6-OMe (85%), 3-NO2, 2,5-OMe (70%), 2-NH2, 6-NO2 (95%), 2-NHCH3, 6-NO2 (85%), 2-NH2, 3,6-OMe (70%), 2-NHCH3, 3,6-OMe (70%), 2-NH(CH)CH3CONHCH3, 3-NO2 (30%), 2-NO2 (>90%)a, 3-NO2 (>90%)a, 4-NO2 (>90%)a

[2]

2 5% Pd/C, Et3N, HCO2H, ~90-100 °C, 1.3-4.5 h

H (100%), 4-CO2CH3 (97%), 2-OCH3 (94%), 4-OCH3 (89%), 4-NHCOCH3 (85%), 2-Br (94%) 3-CH=CHCO2CH3 + 3-(CH2)2CO2CH3 (75%)

[11]

3 Fe(III)/C, NH2NH2.H2O, reflux, 5-28 h

3-CH3 (99%), 4-OCH3 (98%), 2-OMe (98%), 3,4-Me(99%), 4-NHCOCH3 (92%), 4-OC6H5 (98%), 4-OC6H4(4′-NH2) (98%), 2,5-OEt, 4-CONHC6H5 (98%), 2,4-OMe, 5-Cl (97%), 2-OMe, 5-NHCOCH3 (94%), 4-NHC6H4 (4′-OMe) (91%)

[27]

4 Pd Black/HCO2H, rt, 1-12 h and Pd Black/HCO2Na, rt, 15 min-6 h

4-CH3 (92%), 2-OH (91%), 4-OH (90%),2-NH2 (82%), 4-NH2 (81%), 3-NH2 (79%), 4-CO2H (81%), 3-OH (92%), 4-CH2CO2H (81%)

[29]

5 10% Pd-C/HCO2NH4, MeOH, rt, 5-60 min

4-CO2H (52%), 2-OMe, 5-CO2H (75%), 4-CH2CO2H (86%), 4-CO2CH3 (89%), H (76%), 2-F (70%), 4-OMe (93%), 2-NH2, 4-CH3 (79%), 4-CH2C≡N (85%), 3-COC6H5, 4-NH2 (91%), 3-CH2NHC(=NH)NH2 (70%),

[30]

6 Ru3(CO)11, Et3N or Pri2NH,

Diglyme, CO (20atm), H2O, 150 °C, 2 h

2-Cl (>99%), 4-Cl (>99%), 2-Br (>99%), 4-CN (>99%), 4-COC6H5 (>99%)

[33]


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7 RhCl(Ph3)3, Et3SiH, PhMe, 110 °C, 2-6 h

4-OMe (86%), 4-Cl (71%), 3-COMe (71%), 4-CO2Me (49%)

[34]

8 Zro.8Nio.2O2, KOH, PriOH, reflux, 3-6 h

H (96%), 4-CI (85%), 4-COMe, (88%), 2-OMe (86%), 4-COC6H5 (90%)

[35]

9 Al, NH4Cl, MeOH, ))))), 25 ºC, 1-3 h

H (75%), 4-Cl (80%), 2-Cl (70%), 3,4-Cl (75%), 2-NH2 (85%), 3-NH2 (70%), 2-Me (72%), 2-OH (90%), 3-CO2H (70%),

[36]

10 Pd/C, B10H14, 2 drops of AcOH in MeOH, reflux, 0.5-3 h

4-CO2H (97%), 4-CO2Me (96%), 4-CO2CH2C6H5 (91%), 4-NHCOMe (96%), H (90%), 3-Me, 4-Br (81%), 4-Me (91%), 4-CH2CN (95%), 3-CH2OH (94%)

[39]

11 FeCl3·6H2O, NH2NH2.H2O, µW, 30-70 W, 7-10 min

4-OMe (96%), 4-CH3 (89%), 4-Cl (96%), 4-I (91%), 3-OH (92%), 2-OH (81%)

[40]

12 CoHMA, KOH, PriOH, 356 K, 1.5-5 h

H (91%), 2- Cl (83%), 3-Cl (88%), 4-Br (90%), 4-F (84%), 2-Me (67%), 4-OMe (88%), 2-NH2 (92%), 3- NH2 (86%)

[41]

13 NiMCM-41, KOH, PriOH, 356 K, 3.5-5 h

H (93%), 2-CI (85%), 4-Br (91 %), 4-OMe (90%), 2-NH2 (85%), 4-COMe (83%)b, 2-CHO (84%)b, 3-NO2, 4-Me (82%)c, 3-NO2, 4-Cl (84%)c

[42]

14 FeHMA, KOH, PriOH, 356 K, 2.5-3 h

H (92%), 2-CI (79%), 4-Cl (89%), 4-F (82%), 4-Br (85 %), 4-OMe (88%), 2-NH2 (73%), 3-NH2 (80%), 2-Me (70%), 3-Me (85%)

[43]

15 NiHMA, KOH, PriOH, 356 K, 1.5-4 h

H (97%), 2-CI (86%), 3-Cl (90%), 4-Br (93 %), 4-F (91%), 4-OMe (93%), 2-NH2 (89%), 4-Me (89%),4-Me (89%) 4-COMe (92%)b, 2-CHO (84%)b, 3-NO2, 4-Me (87%)c, 3-NO2, 4-Cl (88%)c

[44]

16 PdMCM-41, HCO2NH4, MeOH, 356 K, 30-60 min

H (99%), 2-Me (92%), 3-Me (90%), 3-CO2H (85%), 4-COMe (80%), 3-CHO (82%), 4-OMe (88%), 2-OH (86%), 2-NH2 (87%), 4-CH2CN (83%)

[45]


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Zn, NH4Cl, [bmim][PF6]:H2O (10:1), rt, 7-18 h

H (93%), 4-Me (94%), 2-Me (85%), 4-OMe (85%), 2-OMe (83%), 4-Cl (89%), 4-I (81%), 3-COMe (91%), 3-F, 4-Me (93%), 2, 3-Cl (90%), 4-OH (77%), 4-NH2 (79%)

17

Zn, HCO2NH4, [bmim][BF4]:H2O (10:1) rt, 10-12 h

H (87%), 4-Me (92%), 4-OMe (89%), 2-OMe (81%), 4-I (89%), 3-COMe (90%), 3-F, 4-Me (87%), 2, 3-Cl (89%), 4-NH2 (76%),

[46]

18 Fe powder (nm), H2O, 210 ºC, 2 h

H (95%), 4-Me (96%), 3-OMe (91%), 3-Me (94%), 4-COMe (92%), 4-CO2Et (94%), 4-F (95%), 4-Cl (95%), 4-Br (90%), 2-Cl (89%)

[47]

19

Mg, NH3HCOO+_

, MeOH, rt, 1-3 h

4-I (95%), 3-Cl (94%), 2-Br (96%), 2-OMe (92%), 4-Me (97%), 4-CH=CH2 (95%), 4-CH2CN (93%), 4-CHO (91%), 4-COCH3 (96%), 2-CO2H, 4-Br (94%), 4-CO2H (96%), 4-NHCOCH3 (95%),

[48]

20 Iron oxide hydroxide,

NH3 NH2HCOO+_

, PriOH, reflux, 30-50 min

H (98%), 2-Me (97%), 3-Me (98%), 2-Cl (93%), 3, 4-Cl (98%), 2-OH (96%), 2-NH2 (95%), 4-OMe (99%), 4-CO2Et (95%)

[50]

a Personal communication (I. D. Entwistle), b chemoselective, c regioselective

1.3 REDUCTION OF AZOARENES TO HYDRAZOARENES

The reduction of azo compounds is considered as one of the best way

to synthesize hydrazo compounds. In 1930, Ritter and Ritter [57] reported

the reduction of azo compounds to hydrazo compounds, in their effort to

synthesize mono-acetyl derivatives of the unsymmetrical hydrazobenzenes.

They used zinc dust and glacial acetic acid in boiling alcohol for reduction.

Here they claim that, their method of reduction is more convenient than

that of Jacobson and Lischke [58] in which reduction was accomplished with

zinc dust and sodium hydroxide.

Hayashi et al. [59] demonstrated the catalytic reduction of

4,4'-azopyridine 1,1'-dioxide (I) and 4,4'-azoxypyridine 1,1'-dioxide (II) in


17

methanol using Raney nickel as catalyst at atmospheric temperature and

pressure (Scheme 1.1 and Scheme 1.2). Here, they observed that the

formation of the corresponding hydrazo compound was a result of

absorption of 3 moles of hydrogen. The same reduction with palladium-

carbon as a catalyst afforded the 4,4'-hydrazoypyridine 1,1'-dioxide(VI).

N N

N NO O

H2

Raney-Ni

N N

N N

HN NH

N N

HN NH

N NO O

H2/Pd-C

(V) (IV)

(VI)

(I)

Scheme 1.1

N N

N NO O

H2

Raney-Ni

H2/Pd-C

(II)

O

Raney-Ni

or Pd-C(I)

(V) (IV)

(VI)

Scheme1.2

Cousino [60] has reported his invention of reduction of certain

2,2′-disubstituted azoxybenzenes and azobenzene to corresponding

hydrazobenzenes. According to his invention certain 2,2′- disubstituted

hydrazobenzenes, namely 2,2′- dichlorohydrazobenzene 2,2′-

dimethylhydrazobenezene and 2,2′-dimethoxyhydrazobenzene were

produced from the corresponding 2,2′-disubstituted azoxybenzene or

azobenzene. Here, he used iron filings or powdered iron, lead acetate and

dilute acid (5% HCl) for reduction at the temperatures of about 55º to 65 ºC.

The solvents used are bezene and methanol.

Casewit et al. [61] used Molybdenum(IV) complexes of composition

[MeCpMo(µ-S)]2S2CH2(I) and [MeCpMO(µ-S)(µ-SH)]2(II), where


18

MeCp = CH3C5H4, as homogeneous catalysts for the reduction of a azoarenes

under 2-3 atm of hydrogen at mild temperatures (25 ºC) (Scheme 1.3).

PhN NPh + H2(MeCpMoS)2S2CH2

PhHN NHPh(MeCpMoSSH)2 or

Organic solvent, 25 ºC

Scheme 1.3

Alberti et al [62] reported the reaction of a series of substituted

azoarenes with tributyltin hydride to afford hydrazo compounds with high

chemoselectivity and good to high yields (Scheme 1.4). But, they observed

the formation of mixtures of hydrazo derivatives and N-heterocycles or

cyclic products when, ortho-substituted azoarenes were used i.e., azoarene

bearing substituents such as CN, COOR or CH2OH at ortho to azo function.

ArN NAr' ArHN NHAr'Bu3SnH

benzene, reflux (3-5 h)

Ar = Ph, 3,5-(MeO)2C6H3

Ar' = Ph, 4-MeC6H4, 4-MeOC6H4, 4-ClC6H4, 4-BrC6H44-IC6H4, 4-NCC6H4, 4-MeC(O)C6H4, 3-pyridyl4-MeOC(O)C6H4, 4-HOOCC6H4, PhC(O)OC6H42-IC6H4, 3-IC6H4

Scheme 1.4

Park and Han [63] reported the reduction of various azoarenes and

azoxyarene almost quantitatively to the corresponding hydrazoarenes by

sodium dithionite under mild conditions without the formation of aniline

derivatives, using dioctyl viologen as an electron-transfer catalyst in

acetonitrile-water (Scheme 1.5).

N N

HN

HN

YX

YX

N NYX

NaHSO3 Na2S2O4

OcV+ OcV2+

O

CH3CN- H2O

Where X and Y = H, -Cl, -CH3, -OCH3, -OH, -NO2, -NH2

Scheme1.5


19

Patil et al. [64] also investigated the same approach and observed that

hydrated zirconia has been found to be an efficient and reusable catalyst for

the selective reductions of azoarenes (Scheme 1.6). The product, hydrazo

compounds were achieved in 5-10 hrs at reflux temperature in high yields.

Azo compounds containing other reducible substituents such as -CH3, -Cl,

-CO2H, -NH2, etc, were rapidly reduced to corresponding hydrazo

compounds.

N N ArArZrO2, N2H4 H20

NaHCO3, EtOH

HN

HN ArAr

75 - 90% Scheme 1.6

Khan et al.[46] reported a chemo-selective reduction of azo compounds

in ionic liquids using zinc and ammonium salts (Scheme 1.7). They found

that, azobenzenes were smoothly reduced to hydrazobenzenes with

Zn/HCO2NH4 (aq.) in recyclable [bmim][BF4] without any over reduction to

the corresponding anilines. Recently, Prasad et al. [65,66] reported the

synthesis of hydrazo compounds from azo compounds using Raney-

Ni/H2NNH2.HCO2H and Zn/H2NNH2.HCO2H in methanol at room temperature.

N N ArArHN

HN ArAr

Zn/HCO2NH4

bmimBF4:H2O (10:1), r.t25 min - 1 h 83 - 98%

Ar = Ph, 4-MeC6H4, 2-MeC6H4, 4-ClC6H4

Scheme 1.7

Recently, Yin et al. [67] reported the reduction of azo compounds to

hydrazo compounds in their synthesis of sulfonated diamine isomers,

2,2’-bis(3-sulfopropoxy)benzidine (2,2’-BSPB) and 3,3’-bis(3-

sulfopropoxy)benzidine (3,3’-BSPB) (Scheme 1.8). They used zinc powder in

presence of weak acid to achieve reduction and further, the diamines were

obtained by rearrangement reactions of hydrazo compounds in hydrochloric

acid.

N N

O(CH2)3SO3Na

NaO3S(H2C)3O

Zn/H+ HN

HN

O(CH2)3SO3Na

NaO3S(H2C)3O

O(CH2)3SO3H

HO3S(H2C)3O

NH2H2NH+

Scheme 1.8


20

1.4 REDUCTION OF IMINES TO SECONDARY AMINES

The reduction of imines is a very convenient and explicit route to

the synthesis of substituted amines [68]. Here in this section, the

reduction of imines to secondary amines is discussed.

The Fig 1.1 illustrates a brief classification of the major traditional

methods for the synthesis of secondary amines. Very recently, Salvatore et

al. [69] have given detailed report of secondary amine synthesis. Among all

the methods, complete reduction of certain functionalities using a variety

of reducing agents is considered as one of the most convenient method.

RHN R1

NHR + X R1

Solid Phase synthesis

R NH2 + X R1

N-Alkylation

R NH2 + HO R1

Condensation reactions

RN R1

H

Reduction reactions RN R1

R2

Radical reactions

RN R1

Nu

Addition reactionsR NH2

M

+ X R1Metal-coordinated

reactionsR NR1

PR NH

P

N-Protection

R, R1 = alkyl or aryl

Fig 1.1: Some of the methods for synthesis of secondary amines [68]

Botte et al. [70] reported the reduction of several N-alky and N-aryl

ketimines to the corresponding secondary amines using isopropyl alcohol

and aluminum isopropoxide in the presence of Raney-Ni (Scheme 1.9).

Hoye et al. [71], in their total synthesis of (ent)-korupensamine D, cyclic

imine was reduced using H2 and 10% Pd/C, which gave rise to

cis-configured secondary amine in 93% yield (Scheme 1.10).


21

N(PriO-)3Al, PriOH

Raney-Ni

HN +

HN

Me

Me+ OH

Scheme 1.9

N

MeO

OMe Me

Me

NH

MeO

OMe Me

H2, Pd/C Me

93%

Scheme 1.10

Fu and Lopez [72] have reduced a wide variety of imines to the

corresponding amines using polymethylhydrosiloxane (PMHS) in ethanol at

room temperature in the presence of n-butyltin tris(2-ethylhexanoate) as

the catalyst. Alkene, alkynes, alkyl bromides, epoxides, esters and nitriles

are stable under the reaction conditions. For example,

N-benzylideneaniline cleanly gives N-phenylbenzylamine in 82% yields after

7 h at room temperature (Scheme 1.11). Similarly, titanium based

catalysts in conjunction with PMHS have been used to reduce imines to

secondary amines (Scheme 1.12) [73]. Here, the titanium species is first

reacted with phenylsilane to generate a titanium catalyst. The slow

addition of sec-butylamine results in exchange of amine ligands of the

titanium complex to release the amine product. The same protocol has

been used in highly efficient synthesis of the amine NPS R-568

(Scheme 1.13), a potentially active compound for the treatment of

hyperparathyroidism via reduction of the imine [74].

R1

N

R(H)

R2

SiH

MeO

n

OBuSn

On-Bu 3

10 mol%

EtOH, r.t R1

HN

R(H)

R2

PMHS Scheme 1.11


22

NCH2Ph HN

CH2Ph

1. PhSiH3, Cat. 1 (0.5 mol%)

2. PMHS, iBuNH2

TiF F

Cat. 195%

Scheme 1.12

OMeN

OMeNH

NPS R-56883%

Cl

1 % (R,R)-(EBTHI)TiF2PhSiH3, PyrrolidineMethanol

PMHS

H2NMe

Me

0.035 mL/h55 ºC

Cl

Scheme1.13

Mao and Baker [75] reported the asymmetric transfer hydrogenation

of several heterocylic imines using a chiral rhodium complex,

(R)-Cp*RhCl[(1S,2S)-p-TsNCH(C6H5)CH(C6H5)NH2] (1a, (S,S)-Cp*RhClTsDPEN),

generated from [Cp*RhCl2]2 and (1S,2S)-N-p-toluenesulfonyl-1,2-

diphenylethylenediamine [(S,S)-TsDPEN], in combination with HCO2H-Et3N

as the hydrogen source and have been achieved in up to 99% ee

(Scheme 1.14).

R R'

NR'' Cp*RhClTsDPEN (Cat.)

HCO2H-NEt3 R ∗ R'

NR'' N

NH2

Rh

Ts

Cl

Cat., (S,S)R or R' = alkyl- or arly-R'' = alkyl- or ArSO2-

Scheme 1.14

Barmore et al. [76], in their one-pot reductive amination of nitriles

with DIBAL-H involved trans-imidation by the addition of primary amine

and further reduced to the secondary amine using NaBH4 (Scheme 1.15).

Reduction of imines to secondary amines was achieved using Zn(BH4)2

supported on silica gel in good yields [77].


23

Cl

NOMe

Cl

HN

OMe

NaBH4, EtOH

82% Scheme1.15

Blackwell et al. [78] reduced a wide range of benzaldimines and

ketimines via silyliminium intermediate to the corresponding secondary

amines. In this legend, B(C6F5)3 was employed as a catalyst (5-10 mol%) in

conjunction with PhMe2SiH (Scheme 1.16).

Ar

N

R1+ PhMe2SiH

B(C6F5)3 (5-10%)

PhMe, r.t. 0.5-96 h Ar

HN

R1

57-97%

R2 R2

Scheme 1.16

Addition of HMPA to SmBr2 in THF enables ketimines to be reduced

to the corresponding amines at 20 ºC [79] (Scheme 1.17). Secondary

amines free from the common side products of over alkylation and

carbonyl starting materials have been prepared by transimination of a

resin-bound aldehyde with a solution-phase primary amine to give a

solution-phase imine that undergoes reduction with resin-bound

borohydride to furnish the secondary amine in solution [80] (Scheme

1.18).

N SmBr2 - HMPA

THF

NH

Scheme 1.17

N RR'NH2

BH4

R'HN R

Scheme 1.18

Basu et al. [81] reported a polymer supported reaction procedure

for the reduction of imines. The reduction was accomplished within


24

10-16 hrs with good yields using 10% Pd-C and polymer supported formate

at 70-75 ºC (Scheme 1.19).

R2

R1

XR4

R3

XR2 R4

R1 R3

R1 = R2 = Ph, Ar, HX = C, NR3 = R4 = CN, COOEt, COOMe, NHBoc, H, Ph

N+R3HCOO-

Scheme 1.19

Malkov et al. [82] reported asymmetric reduction of ketimines with

trichlorosilane catalyzed by a new N-methyl L-valine derived Lewis basic

organocatalyst (Scheme 1.20).

Ar

NPh Cl3SiH

Cat.*

Toluene, r.t. Ar ∗

HNPh

(92% e.e.)

∗N

HO

O

HN

Me

Cat.*

Scheme 1.20

Recently, Nolin et al. [83] described the development of a novel

Re(V)-oxo complex for the catalytic enantioselective reduction of imines to

the corresponding secondary amines. Here, they reports that the catalyst

system operates well with either dimethylphenylsilane (DMPS-H) or

diphenylmethylsilane (DPMS-H) as hydride source (Scheme 1.21).

R R'

NP(O)Ph2 3 mol% Cat.

DMPS-H, CH2Cl2, r.t R R'

HNP(O)Ph2

NRe

NO

O

O

OPPh3

ClCl

R

R

NC

R= 4-t-Bu-PhCat.

Scheme 1.21


25

It has been the central focus in modern organic synthesis to develop

highly efficient catalytic processes for the syntheses of natural and

unnatural compounds of medicinal interest or intermediates useful for

functional materials. One of the most attractive approaches to such aims is

to apply transition metal-catalyzed reductive cyclization reactions for the

transformations of simple starting materials into monocyclic, bicyclic, and

polycyclic scaffolds that can be further elaborated into specific targets. In

this account, we brief the synthesis of indolones (oxindoles) and quinolones

(quinolinones) in the following section.

1.5 SYNTHESIS OF INDOLONES AND QUINOLONES

In 1945, Sumpter reported a detailed survey on indolone (oxindole)

synthesis [84]. According him, the first reports of synthesis of oxindole was

by Baeyer in the year 1866 and 1868. Baeyer and Knop [85] synthesized

indolone by the reduction of isatin. They obtained 3-hydroxyindolin-2-one

(dioxindole) upon reducing isatin with sodium amalgam in alkaline medium.

Further reduction of dioxindole with tin and mineral acids or sodium

amalgam in acid medium gave oxindole. Later, there are several reports on

reduction of isatin to oxindole using various reagent systems. But, the first

synthesis of oxindole, other than by the reduction of isatin was again by

Baeyer [86] through the reduction of 2-nitrophenylacetic acid with tin and

hydrochloric acid (Scheme 1.22).

CH2COOH

NO2

NH

O

NO

OH

2-Nitrophenylacetic acid

Oxindole

1-Hydroxyoxindole Scheme 1.22

Di Carlo [87] found that catalytic reduction of o-nitrophenylacetic

acid with Adams catalyst gave oxindole in good yield. Under certain

conditions some 1-hydroxyoxindole was obtained as a by-product. Later on


26

Walker [88] utilized a similar protocol for the synthesis of

5,6-dimethoxyoxindoles. The process was a low-pressure hydrogenation of

4,5-dimethoxy-2-nitrophenylacetic acid or ester in presence of palladium-

charcoal. He obtained amino ester upon hydrogenation of nitro-ester in

ethyl acetate at room temperature in presence of palladium-charcoal, but

on using acetic acid as solvent at an elevated temperature, 80 ºC, he found

the ring closure to the oxindole (Scheme 1.23).

NO2

COOEtH3CO

H3CO

3H2

NH2

COOEtH3CO

H3CO

3H2 (H+)

H3CO

H3CO NH

O

Pd-C, Ethyl acetate

Pd-C,Acetic acid, 80ºC

Scheme 1.23

Wright, Jr., and Collins [89] prepared a series of oxindoles and

1-hydroxyindoles by the zinc and sulfuric acid reduction of the appropriate

o-nitrophenylacetic acids. Here, they obtained 1-hydroxyindolone as the

major product and oxindole as a by-product (Scheme 1.24). In an attempt

to improve the yields of 1-hydroxyoxindole, they have tried the reduction

with (a) zinc and calcium chloride (b) calcium sulfhydrate. But, yield was

15% in the first case where as in second case no product. In continuation,

they synthesized 5-bromooxindole through 1-hydroxyoxindole

(Scheme 1.25).

CH3

NO2

Rdiethyl oxalate

sodium methylate

HCl

H2ONO2

RCOOH

O

H2O2

NO2

RCOOH

Zn H2SO4

NOR

NH

OR

OH

+

Scheme 1.24


27

NO

OCH3

NO

OH

2HBr

HBr

NH

O

+ H2O + Br2

NH

O

NH

O

Br2

Br

Scheme 1.25

Simet [90] utilized Baeyer method of oxindole synthesis i.e., acid

reduction of the appropriately substituted 2-nitrophenylacetic acid, in the

preparation of 6-trifluoromethylisatin from the corresponding oxindole

(Scheme 1.26).

ClNO2

CF3

1. CH2(COOEt)2NaOEt

2. aq. NaOH3. aq. HCl

CF3

NO2

CH2COOH

NH

OF3C N

H

OF3C

O1. Br2, CCl42. aq. NaOH

3. aq. HCl

Sn

aq. HCl

Scheme 1.26

Beckett et al. [91] have prepared a series of oxindole derivatives

substituted in the aromatic ring and their N-Me homologues. They

synthesized appropriate o-nitrophenylacetic acid and performed catalytic

reduction using Pd/C to get the corresponding cyclized product.

Gassman and van Bergen [92] reported a new method of oxindole

synthesis as shown below. (Scheme 1.27, Table 1.2). Later on Wright et al.

[93] modified the Gassman oxindole synthesis. They described the procedure

that proceeds through anilines and ethyl(methylsulfinyl)acetate, using oxalyl

chloride to activate the sulfoxide to fecilitate the formation of the key N-S

bonded intermediate (Scheme 1.28).


28

XNR

H

(1) (CH3)3COCl, CH2Cl2, -65 ºC, 5-10 min(2) CH3SCH2CO2C2H5, -65 ºC, 1 hr

(3) Et3N

CHCO2C2H5

SCH3

R

HX

62%

XN

O

SCH3H

R

III

84%III

XN

O

HH

R76%IV

or H+

Ra-Ni

Scheme 1.27

Table 1.2: Yields obtained in conversion of anilines (I) to oxindoles (IV) with ethyl methylthioacetate.

Aniline X R Methylthio- -oxindole

Yield of (III) (%) Oxindole Yield of

(IV) (%) (Ia) H H (IIIa) 84 (IVa) 76 (Ib) p-CH3 H (IIIb) 34 (IVb) 55 (Ic) o-CH3 H (IIIc) 67 (IVc) 72 (Id) H CH3 (IIId) 46 (IVd) 77 (Ie) p-CO2C2H5,

o-CH3 H (IIIe) 66 (IVe) 67

(If) p-NO2 H (IIIf) 51 a a No attempt was made to carry out a Raney-nickel desufurization of (IVf)

CO2EtH3CS

CO2EtH3CS+O-

CO2EtH3CS+Cl

CO2EtH3CS+N

C6H5R

NO

SCH3

R

a

b

c d

(a) Cl2, CH2Cl2, -78 ºC (b) ClCOCOCl, CH2Cl2, -78 ºC (c) C6H5NHR, -78 ºC (d) Et3N, 20 ºC then HCl

Scheme 1.28

Cortese and Hack [11] reported the formation of saturated lactams

i.e., oxindole and quinolinone on reduction of o-nitrophenylacetic acid and

o-nitrocinnamic acid respectively. They used triethylammonium formate

with palladium on charcoal as catalyst for reduction at boiling temperature

of the reaction mixture (~90-100 ºC) (Scheme 1.29). The product,


29

quinolinone obtained was in 72% yield where as the other one was a 1:1

mixture of oxindole and o-aminophenylacetic acid. Sublimation of the

product mixture produced the oxindole in 75% yield.

NO2

CO2H

+ Et3NH+HCOO- Pd/C

-H2O, -CO2-Et3N

HN O

Scheme 1.29

RanjanBabu et al. [94] synthesized various 2-indolinones (oxindoles)

by reductive cyclization of α-(2-nitroaryl)acetic acid derivatives in 20% ethyl

acetate in ethanol at 40-59 psi of hydrogen. Depending on the catalyst used,

they observed the dechlorination with certain chlorinated substrates.

Hence, they have used sulfided platinum and palladium carbon as catalysts

and obtained moderate to good yields (Table 1.3). They also reported the

catalytic reduction of the γ-butyrolactone adducts to obtain

3-(2-hydroxyethyl)-2-indolinones (Table 1.4).

Table 1.3: Synthesis of oxindoles by RanjanBabu et al [94].

CO2Me

NO2

X

ZY

R

X

ZY

[H]

NO

R

H Starting material Entry

X Y Z R Method* Yield % (2-indolinone)

1 H H Cl H A 76 2 H Cl H H A 80 3 Cl H H H A 60 4 H H H Me B 50 5 H Cl H Me B 74 6 Cl Cl H Me B 54 7 H Me H Me B 95 8 H OMe H Me B 68

*Method A. Pt/S/C/H2 B. Pd/C/H2


30

Table 1.4: Synthesis of 3-(2-Hydroxyethyl)-2-indolinones

NO2

O

O

XReduction

N

XO

R

OH

Starting material Indolinone Entry

X Method

R Yield (%) 1 H Pd/C/H2 H 52 2 Me Pd/C/H2 H 45 3 F Pd/C/H2 H 37 4 Cl Pd/C/H2 OH 63 5 Cl Fe/AcOH H 28

Quallich and Morrissey [95] reported a general three-step synthesis of

oxindoles which is formulated on employing a malonate addition to a

substituted α-halonitrobenzene to control regiochemistry (Scheme 1.30)

X

NO2

R

DMSO/NaHCH2(CO2Me)225-100 ºC, 1h

33-85% NO2

R

CO2Me

CO2Me

DMSO/LiClH2O100 ºC, 3h

56-86%

NO2

RCO2Me

Fe/AcOH100 ºC, 1h

60-93%R

NH

O

X = Cl, Br, F

R = 5-Cl, 6-Cl, 6-OMe, 6-Br, 5-F, 6-F, 4-Cl

Scheme 1.30

Boix et al. [96] have prepared indole and quinoline derivatives by

reduction of suitably functionalised o-nitroarenes with zinc in near-critical

water at 250 ºC. In the process they observed the formation of

hydroquinoline or hydroquinolinone depending upon the substrate used.

They found that the dihydroquinolinone was the major product upon using

o-nitrocinnamic acid. Hennessy and Buchwald [97] have developed a novel

variant of the Friedel-Crafts procedure using palladium-catalyzed C-H

functionalization. They used the combination of catalytic amounts of

palladium acetate, 2-(di-tert-butylphosphino)biphenyl as a ligand and


31

triethylamine as base to convert α-chloroacetanilides to oxindoles in high

yields (Scheme 1.31).

R1

NR2

OCl

1-3 mol% Pd(OAc)22-6 mol% 1

1.5 equiv NEt3toluene, 80 ºC2.5 - 6 h

R1

NR2

O PBu2

1

Scheme 1.31

Recently, Poondra and Turner [98] reported the microwave-assisted

synthesis of N-substituted oxindoles. The method is a two-step process

which involves initial microwave-assisted amide bond formation between

2-halo-arylacetic acids and various alkylamines and anilines, followed by a

palladium catalyzed intramolecular amidation under aqueous conditions.

The procedure can be carried out as one-pot process without isolation of the

intermediate amide, while using alkyamines (Scheme 1.32). In optimizing

the reaction conditions for palladium catalyzed intramolecular amidation

they have screened various phosphine ligands in combination of palladium

source/solvent/base (NaOH) and found that the ligand shown bellow is

suitable one.

R1

X

OH

O+ H2N R R1

NO

R

(1) MW, 300W, 150 ºC, 30 min

(2) Pd(OAc)2 /LigandBase, H2O /Toluene or TolueneMW, 75W, 100 ºC, 30 minR = alky, aryl

X = Br, Cl

i-Pri-PrPCy2

i-Pr

ligand (6 mol%)

Scheme 1.32


32

1.6 SYNTHESIS OF AMIDES OF AMINO ACIDS AND PEPTIDES

The abundance of the amide function in both natural products and

man-made compounds shows the significance of the amide functional group

and their synthesis. Although many methods are available to synthesize

amide functional group, there remains the opportunity to develop new

techniques that may be more efficient.

One of the most adopted methods to synthesize amides is solid phase

synthesis through cleavable linkers. James [99] has published a detailed

report on linkers that are commonly used for solid phase organic synthesis.

Marzinzik and Felder [100] reported a procedure that, the nitrogen of the

linker is acylated by a carboxylic acid using a range of acylating reagents

such as DIC/DMAP or HOBt/BOP, although more forcing conditions may be

required to prepare bulky amides. Cleavage is typically achieved with 50%

TFA/DCM, although lower concentrations of TFA may be used, e.g. 20%

TFA/DCM (Scheme 1.33).

NH2

OMe

OMe

acylation

NH

OMe

OMe

O

R

H2N R

O20-50% TFA/DCM

Scheme 1.33

Sieber: the amine of the Sieber linker can be easily acylated [101] and the

amide is very acid labile, cleaved in 1% TFA/DCM [102] (Scheme 1.34).

O

ONH2

O

OHN

RCO2H

acylation

R

O

H2N R

O1% TFA/DCM

Scheme 1.34

PAL: The PAL linker [103,104] can be used to generate primary amide by

cleaving with 70% TFA/DCM (Scheme 1.35).

Benzhydryl: The benzhydryl amine and related p-methylbenzhydryl amine

linkers are also used for the preparation of primary amides. Here, due to its

electron richness, the strong acid HF is used for cleavage (Scheme 1.36)

[105,106].


33

NH

OO4

OMe

OMe

NH2

PAL linker

acylation NH

OO4

OMe

OMe

HN R

O

H2N R

O70% TFA/DCM

Scheme 1.35

NH2

acylation

NHO

R

H2N R

OHF

Scheme 1.36

Ester Linker: The benzylic ester linker can be treated with an unhindered

amine to cleave the product as an amide incorporating the amine used for

the cleavage (Scheme 1.37). Primary amides are obtained by the aminolysis

of the HMB [107] and glycolamido [108,109] linkers.

HN

O

O

O

R NH3

vapour or in MeOH

HMB

H2N R

O NH3

vapour

HN

OO

O

R

Glycolamido linker Scheme 1.37

Kaiser Linker: Kaiser’s oxime linker has been used to couple carboxylic

acids, which then may be cleaved with ammonia to obtain primary amide

(Scheme 1.38) [110,111].

O R

O

NO2

NH3H2N R

O

Kaiser linker

Scheme 1.37

Photolabile: 2-Nitrobenzyl amine linkers have been used as photolabile

amide linkers (Scheme 1.38) [112]. 2-Nitrobenzhydryl amine linker is used

as improvised methods to obtain primary amides (Scheme 1.39) [113].


34

O

HN

NO2

NH

Peptide

O hv Peptide

O

H2N

Scheme 1.38

HNPeptide

O

O2N

hv, 350 nm

MeOH/DMFH2N Peptide

OO2N

+O

Scheme 1.39

Peptides prepared on Pepsyn KB resin (polydimethylacrylamide Kieselguhr

resin) were cleaved with ammonia/tetrahydrofuran vapour to get the

peptide amide (Scheme 1.40) [114].

Peptide O

O

O

1) NH3/THF vapour

2) Elution Peptide NH2

O

Scheme 1.40

Pozdnev [115] reported the application di-tert-butyl pyrocarbonate as

condensing reagent in the presence of pyridine and ammonium

hydrogencarbonate for the preparation of amides of protected amino acids

and peptides (Scheme 1.41).

RCOOH Py + (ButOCO)2O [RCO-O-COOBut] + ButOH + CO2

RCONH2 + ButOH +CO2

+(NH3)

Scheme 1.41

Scott et al. [116] synthesized amino amides and peptide amides with

unnatural side chains using solid-phase chemistry, from glycine attached

directly (or through an intervening peptide sequence) to a Rink resin. The

glycine is converted to an activated benzophenone imine derivative,


35

followed by C-alkylation and hydrolysis. Cleavage with trifluoroacetic acid

produced the final amide products (Scheme 1.42).

H2N NH

O R HN

On

a) Ph2C=NH NNH

O R HN

On

Ph

Ph

b) R1X, Base NNH

O R HN

On

Ph

Ph R1

c) H+/H2O

H2N NH

O R HN

On

R1

d) R2CO2H, HOBT/DICor FmocCl, DIEAe) TFA

HN

NH

O RNH2

On

R1

R2

O

n = 0-2R = amino acid side chainR1 = "Unnatural" side chain introduced by alkylationR2 = capping group or AA

Scheme 1.42

Cros et al. [117] described new strategy for solid-phase synthesis of

C-terminal peptide amides based on the use of N-tetrachlorophthaloyl

protected amino acids with acid-labile side-chain protection (Scheme 1.43).

Recently, Chinchilla et al. [118] prepared new ammonium and

alkylammonium salts derived from a polymeric N-hydroxysuccinimide

(P-HOSu) and used for amidation of carboxylic acids and amino acids

mediated by 1-ethyl-3-(3’-dimethylamino-propyl)carbodiimide hydrochloride

(EDC) (Scheme 1.44).

Fmoc-PAL-PEG-PS

1) Piperidine:DMF (3:7)2)TCP-Ala-OH (3 equiv)

DIPCDI (3 equiv)HOAt (3 equiv)

TCP-Ala-PAL-PEG-PS

1) Hydrazine:DMF (3:7)2)TCP-Asp(OtBu)-OH (3 equiv)

DIPCDI (3 equiv)HOAt (3 equiv)

TCP-Asp(OtBu)-Ala-PAL-PEG-PS

sequential deprotectionsand couplings TCP-Gly-Gly-Asp(OtBu)-Ala-PAL-PEG-PS

TFA-H20 (19:1)1) hydrazine:DMF (3:17)2) TFA-H20 (19:1)

TCP-Gly-Gly-Asp-Ala-NH2 H-Gly-Gly-Asp-Ala-NH2

O

O

HC CO2HR

ClCl

ClCl

R = amino acid side-chain

N -TCP procted amino acid

Scheme 1.43


36

N OO

Ph

n RNH2

N OO

Ph

n

OH ONH3R

R = H, Me, Et

EDC, Carboxylic acidor Cbz-, Fmoc-,Boc-amino acid

MeOH, reflux for 1 dayAmide

Scheme 1.44


37

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reductive functional group...

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