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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,
REVIEW: Reductive Functional Group Transformations Chapter 1
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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
REVIEW: Reductive Functional Group Transformations Chapter 1
4
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
REVIEW: Reductive Functional Group Transformations Chapter 1
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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
REVIEW: Reductive Functional Group Transformations Chapter 1
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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
REVIEW: Reductive Functional Group Transformations Chapter 1
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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
REVIEW: Reductive Functional Group Transformations Chapter 1
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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
REVIEW: Reductive Functional Group Transformations Chapter 1
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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
REVIEW: Reductive Functional Group Transformations Chapter 1
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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.
REVIEW: Reductive Functional Group Transformations Chapter 1
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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
REVIEW: Reductive Functional Group Transformations Chapter 1
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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
REVIEW: Reductive Functional Group Transformations Chapter 1
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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].
REVIEW: Reductive Functional Group Transformations Chapter 1
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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]
REVIEW: Reductive Functional Group Transformations Chapter 1
15
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]
REVIEW: Reductive Functional Group Transformations Chapter 1
16
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
REVIEW: Reductive Functional Group Transformations Chapter 1
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
REVIEW: Reductive Functional Group Transformations Chapter 1
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
REVIEW: Reductive Functional Group Transformations Chapter 1
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
REVIEW: Reductive Functional Group Transformations Chapter 1
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).
REVIEW: Reductive Functional Group Transformations Chapter 1
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
REVIEW: Reductive Functional Group Transformations Chapter 1
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].
REVIEW: Reductive Functional Group Transformations Chapter 1
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
REVIEW: Reductive Functional Group Transformations Chapter 1
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
REVIEW: Reductive Functional Group Transformations Chapter 1
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
REVIEW: Reductive Functional Group Transformations Chapter 1
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
REVIEW: Reductive Functional Group Transformations Chapter 1
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).
REVIEW: Reductive Functional Group Transformations Chapter 1
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,
REVIEW: Reductive Functional Group Transformations Chapter 1
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
REVIEW: Reductive Functional Group Transformations Chapter 1
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
REVIEW: Reductive Functional Group Transformations Chapter 1
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
REVIEW: Reductive Functional Group Transformations Chapter 1
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].
REVIEW: Reductive Functional Group Transformations Chapter 1
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].
REVIEW: Reductive Functional Group Transformations Chapter 1
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,
REVIEW: Reductive Functional Group Transformations Chapter 1
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
REVIEW: Reductive Functional Group Transformations Chapter 1
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
REVIEW: Reductive Functional Group Transformations Chapter 1
37
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