CERTIFICATE
Scheme 2.32: Synthetic path for the formation of 2-substituted benzimidazoles
3.1 Introduction
Alcohols are very versatile chemicals that have been commonly used in organic transformations and chemical industries.1-2 The formation of new C−C bonds are not only important in organic chemistry but also acts as an alternative carbon source in petrochemical industry. The major concern is to synthesize alcohols through an alternative pathway. The traditional process used for the production of -alkylated alcohols consist of a multistep synthetic pathway. This process led to the generation of a stoichiometric amount of waste product3-5 along with the consumption of expensive and toxic reagents, and strong bases3-5 (Scheme 3.1).
Scheme 3.1: Traditional approach to C-alkylation reaction.6-7
Among the various protocols, transition metal-catalyzed C−C bond formation via -alkylation of alcohols has garnered a lot of attention. Accounting for an environment friendly process, the use of alcohols to form higher -alkylated alcohols via an acceptorless dehydrogenative coupling proves to be an attractive approach. In this process: initial dehydrogenation of both (primary and secondary) alcohols to the corresponding carbonyl compounds is followed by aldol condensation to form corresponding unsaturated ketones which eventually gets hydrogenated to afford -alkylated alcohols (Scheme 3.2).
Scheme 3.2: A greener strategy towards C-alkylation.7
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Kanu Das, Ph.D Thesis, IIT Guwahati 102 Scheme 3.3: C-alkylation reaction catalyzed by copper.8
The dehydrogenation of alcohols in anaerobic conditions is widely explored by employing various transition metals.9-11 In aerobic condition, hydrogen-borrowing strategy for the dehydrogenation of alcohol holds some drawbacks involving a metal hydride species (i.e MH2; Scheme 3.2) as it seems to be air sensitive or not readily formed. In fact, C-alkylation via hydrogen-borrowing methodology under mild reaction conditions is more desirable in organic synthesis. In general, transition metal catalyzed C-alkylation reaction involves inert condition with a pre-coordinated ligand to the metal center. Xu and co-workers investigated the - alkylation of secondary alcohols and -alkylation of ketones using a ligand-free copper catalyst (Scheme 3.3).8 Their methodology involves an earth abundant transition metal (copper) that holds wide scope to provide an alternative route in synthetic chemistry.
Scheme 3.4: Over oxidation of product during pincer-Ru catalyzed C-alkylation reaction.12 Achard and co-workers demonstrated the use of bi/tri-dentate phosphine pyridine ligand-based metal complexes to form ester through alcohol dehydrogenation. Interestingly, the use of complex 3.5 resulted in -alkylated ketone via dehydrogenative cross-coupling of secondary alcohol with primary alcohol along with the formation of a trace amount of -alkylated alcohol (Scheme 3.4).12 While, the -alkylated ketones could be obtained either from primary alcohols with a ketone or secondary alcohols with an aldehyde in the presence of a base and catalyst, the sequential de/hydrogenation strategy utilized here to synthesize -alkylated ketone directly is an effective alternative pathway. This implies that the alkylation of secondary alcohol with
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Kanu Das, Ph.D Thesis, IIT Guwahati 103 primary alcohols directly produces either -alkylated alcohol or takes part in further dehydrogenation of -alkylated alcohol to form the -alkylated ketone.
Scheme 3.5: Ruthenium catalyzed formation of -alkylated ketones.13
Chen and co-workers demonstrated ruthenium catalyst based on NNN tridentate ligand, which involves bifunctional uncoordinated pyridyl group in catalytic system of β-alkylation of secondary alcohols with primary alcohols.14 The reactivity mainly depends on the nucleophilicity of the 2-hydroxypryrdine group (one of the ligating arm), which reflects the systematic involvement of metal-ligand co-operativity in the alkylation reaction. Similarly, pyridines, quinolines and pyrroles have been synthesized by the same NNN-Ru catalyzed acceptorless dehydrogenation.15 An analogous Ru-catalyzed thiazolium group-containing ligand system demonstrated α-alkylation of ketones with primary alcohols, giving up to 1840 TON with 3680 TO/h (Scheme 3.5).13
Scheme 3.6: Ruthenium catalyzed -alkylation of alcohols.16
Cho first demonstrated the dichlorotris(triphenylphosphine)ruthenium(II) catalyzed - alkylation of secondary alcohols with primary alcohols in the presence of 1-dodcene (Scheme 3.6).16 This protocol selectively afforded regioselective -alkylation of secondary alcohols with primary alcohols with a variety of substrate scope (including aryl methyl, alkyl methyl, and cyclic carbinols, along with alkyl methyl carbinols).
In order to explore this process, several transition metal complexes based on Ir,17-26 Rh,27 Ru,6,
13, 16, 28-32 Pd,33 Mn,34-35 Co,36 Fe,37 Ni,38 and Cu8 were used significantly (Figure 3.1). Sun and
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Kanu Das, Ph.D Thesis, IIT Guwahati 104 co-workers demonstrated the inexpensive, environmentally benign iron complex 3.10 catalyzed -alkylation of secondary alcohols with primary alcohols using catalytic amount of NaOH without any hydrogen acceptors or phosphorus based ligands.37 Later, Li and Lang described the versatility of the nickel-thiolate-based cluster (3.11) system in the C-alkylation reaction. The C–C cross-coupling of secondary and primary alcohols to α,β-unsaturated ketones, α-alkylated ketones or β-alkylated secondary alcohols under mild conditions has multiple chemoselectivities.38 Xu and co-workers reported the ligand-free copper catalysis under aerobic condition which exhibited superior catalytic activity.8 They deduced a new mechanism for C-alkylation reactions via the Meerwein-Pondorf-Verley type transition state rather than involvement of copper-hydride species.39 Similarly, Kempe,36 Pullarkat,19 Saito33 and Maheswaran27 also reported the C-alkylation reaction of secondary alcohols with primary alcohols using the hydrogen-borrowing methodology. However, ruthenium and iridium-based complexes have shown higher reactivity and selectivity than other transition metals. Notably, several complexes have been used in -alkylation of secondary alcohols using pincer-Ru complexes.
Figure 3.1: Reported catalytic systems for the -alkylation of secondary alcohols with primary alcohols.
Gülcemal and co-workers reported the imidazol-2-ylidene ligand-based iridium(I) 3.13 catalyzed β-alkylation of secondary alcohols with primary alcohols. This simple catalytic
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Kanu Das, Ph.D Thesis, IIT Guwahati 105 system provided the β-alkylated alcohols (including cholesterol derivatives) with good yields under a very low loading of the catalyst 3.13 (Scheme 3.7).40 The catalyst 3.13 achieved up to 940000 TON with a catalytic amount of NaOH or KOH under aerobic conditions via hydrogen- borrowing strategy.
Scheme 3.7: -alkylation of secondary alcohols investigated using a Ir-catalyst.40
Bera and co-workers reported Ir-N-heterocyclic carbene 3.14 catalyzed -alkylation of secondary alcohols with primary alcohols. The complex 3.14 demonstrated remarkable activity due to pyridyl(benzamide)-functionalized NHC backbone, which involves dearomatization/aromatization of pyridine backbone during catalysis. These catalytic systems demonstrated a wide range of substrate scope under low base and catalyst loading within a short reaction time (Scheme 3.8).41 The same methodology, was applied to the α-alkylation of ketones using primary alcohols in addition to the synthesis of quinoline and lactone derivatives.41
Scheme 3.8: -alkylation of secondary alcohols with primary alcohols catalyzed by a Ir- complex.41
Thus, catalytic, one-pot acceptorless coupling of a mixture of alcohols (primary and secondary) gives rise to high carbon-containing alcohols and ketones. Following the same reaction methodology, Gelman and co-workers reported an efficient and selective synthesis of - alkylated ketones via cross-coupling of secondary alcohols with primary/secondary alcohols.
The ligand-metal cooperation is presumed to be involved in the catalytic cycle which operates via dehydrogenation and hydrogenation pathway to achieve a maximum of 48 turnovers (TON) (Scheme 3.9).42
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Kanu Das, Ph.D Thesis, IIT Guwahati 106 Scheme 3.9: Ruthenium catalyzed synthesis of -alkylated ketones from secondary alcohols with primary/secondary alcohols.42
Scheme 3.10: Pincer-ruthenium catalyzed -alkylation of secondary alcohols with primary alcohols.25
Though NNN 2,2:6,2-terpyridine (terpy) ligand is considered as a strong -acceptor relative to other N-donors ligands,43 it also has oxidatively and thermally robust properties.44 Despite the incompatible nature of terpy ligands in transition metal complex systems, it offers a variety of catalytic organic transformations.45 In this regard, Crabtree and co-workers reported - alkylation of secondary alcohols with primary alcohols based on terpy pincer-ruthenium catalyst (Scheme 3.10).25 The use of 20 mol % KOH resulted in the complete conversion to alkylated products with a maximum of 95 TON along with formation of H2O as a byproduct.
Scheme 3.11: Pincer-ruthenium catalyzed -alkylation of secondary alcohols with primary alcohols.6
Similarly, introducing trifluoromethylated molecules to the ligand system has provided versatile applications in catalysis because of the innate qualities of the CF3 group (like high electronegativity, lipophilicity and H-bond formation ability).46 In this context, Yu and co-
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Kanu Das, Ph.D Thesis, IIT Guwahati 107 workers reported the β-alkylation of secondary alcohols with primary alcohols through a hydrogen borrowing pathway and achieved up to 93 TON (Scheme 3.11).6 In mechanistic studies, they proved that the precatalyst Ru(III) initially gets converted to Ru(II) species in the presence of KOH.47
Scheme 3.12: Ruthenium catalyzed C-alkylation reaction.28
Kundu and co-workers reported a series of pincer-ruthenium catalysts for -alkylation of secondary alcohols with primary alcohols. Upon significantly lowering the catalyst loading, the NHC ligand-based NNC pincer-ruthenium complex 3.20 provided a very high turnover of 288000 for the β-alkylation reaction.30 They performed the reaction efficiently under solvent- free conditions with a large scope (towards aromatic, aliphatic and heterocyclic alcohols).
Similarly, they demonstrated bifunctional metal-ligand cooperativity in complex 3.21 for the β-alkylation of secondary alcohols and primary alcohols with high selectivity while achieving 31500 TON.31 They extended the above protocol to the direct synthesis of α-alkylated nitriles starting from nitrile and alcohols. Generally, a toxic alkyl halide, strong base and harmful cyanating (KCN or NaCN) agent is required for the synthesis of α-alkylated nitriles which leads to stoichiometric amounts of waste.48-49 The complex 3.22 showed excellent reactivity in α- alkylation of acetonitrile and arylacetonitriles with alcohols which provided up to 190 TON (Scheme 3.12).28
Ghosh and co-workers reported an amido-functionalized ruthenium carbene complex 3.25 catalyzed -alkylation of secondary alcohols with primary alcohols.50 They also demonstrated
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Kanu Das, Ph.D Thesis, IIT Guwahati 108 that a similar cationic picolyl functionalized NHC ruthenium complex exhibited a comparable reactivity towards C-alkylation (Scheme 3.13).50 The catalyst 3.25 was detected as a hydride intermediate and it remained active till 120 h.
Scheme 3.13: Ruthenium-carbene catalyzed C-alkylation reaction.50
Cycloalkanes are omnipresent in natural and pharmaceutical products. The building block of these products could be synthesized through various pathways, like Diels-Alder51 cycloaddition, Wurtz reaction52 or Michael reaction.53 Generally, all these approaches have some drawbacks, involve multistep procedures, and suffer from regio- or stereoselectivity.54 However, Quadrelli and co-workers introduced an earth-abundant PNP based pincer- manganese 3.26 that catalyzed the synthesis of alcohol-containing cyclohexyl compounds through C-alkylation methodology (Scheme 3.14).55 Initially, 1,5-pentanediol derivative dehydrogenates to the corresponding aldehyde, which takes part in the intermolecular aldol condensation reaction with the dehydrogenated secondary alcohol (ketone). This is followed by an intramolecular aldol condensation resulting in cyclohexyl containing secondary alcohol via a re-hydrogenation. Notably, this concept is widely applicable for various substrates on aromatic groups as well as aliphatic parts. Basically, this molecular design is an engineering approach to synthesize direct consecutive C−C bond formation via hydrogen-borrowing strategy.
Scheme 3.14: C-alkylation reaction leading to the formation of cyclohexane derivatives starting from primary diols.55
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