Formation of C-N bonds is essential in the synthesis of many fine chemicals and pharmaceuticals. 1 Undoubtedly, N-alkylation reactions are key synthetic tools to form C-N bonds. The various methods available span classical reactions such as amination of halides 2 and reductive amination 3 to modern methods like catalytic coupling of amines with aryl halides 4 and hydroamination. 5 One of the more promising strategies is the hydrogen borrowing coupling of amines with alcohols (Scheme 1). 6 This sequence consists of three steps: (1) a dehydrogenation step, such as alcohol to carbonyl conversion by metal catalysis to form a metal hydride; (2) a condensation reaction between the intermediate carbonyl compound and an amine to make an imine; and (3) a hydrogenation step in which the intermediate metal hydride reduces the imine to an amine: the sequence is like reductive amination, except that the aldehyde and hydride reagent are generated in situ. Hydrogen borrowing is not only a cost-effective method with widely available feedstocks (amines and alcohols), but it is atom economical and green, with water as the sole by-product. Various homogenous and heterogenous metal catalysts and biocatalysts are reported to catalyze these reactions; 7 but ruthenium-8 and iridium-based 9 complexes are the most common ones. This review aims to (1) present an overview of the applications of hydrogen borrowing reactions to access N-heterocycles that are pharmaceutical intermediates or biologically active compounds; (2) compare their advantages and limitations with other N-alkylation reactions; (3) discuss current challenges and future prospects for industrial application.
The C-N bond is ubiquitous in biologically active compounds and natural products. As an efficient tool to make C-N bonds, hydrogen borrowing reactions have significant potential for synthesizing pharmaceutical intermediates and natural
R OH R O R N R1 R N H R1 [M] [MH2] R1NH2 H2O Hydrogen Borrow Hydrogen Return Base Anju Nalikezhathu* a Travis J. Williams* b
products, yet to our view, this potential remains largely unrealized in industrial application.
Academic investigators have widely explored the breadth of hydrogen borrowing reactions with different amine and alcohol substrates with some reports for API (Active Pharmaceutical Ingredient) or natural product syntheses. Newton and coworkers surveyed the scope and limitation of a hydrogen borrowing approach to N-alkylation, 10 the most common transformation required for an API synthesis in industrial applications. Their study demonstrates the formation of various pharmaceutical intermediates by different coupling reactions, and it highlights several key drawbacks with current hydrogen borrowing amination systems, such as high catalyst loading, poor turnover, catalyst poisoning by substrate, and catalyst contamination that are effectively limiting the use of the reaction in the preparation of APIs. Still, numerous high impact examples of hydrogen borrowing amination have appeared in the pharmaceutical synthetic literature, and we highlight several here.
Cinnarizine is an antivertigo and antihistamine drug used to treat nausea caused by motion sickness, vertigo, and tinnitus associated with Ménière's disease and other middle ear diseases. 11 Sundararaju and co-workers synthesized cinnarizine by applying a hydrogen borrowing strategy that they developed for the construction of allylic amines from allylic alcohols (Scheme 2). 12 They used Knölker's iron complex (C1) 13 to couple commercially available cinnamyl alcohol and 1benzydrylpiperazine in the presence of Me3NO to afford cinnarizine in 62% yield. The role of Me3NO in this case is oxidative decarbonylation of one of iron's carbonyl ligands without oxidation at the metal. 14 Scheme 2 Syntheses of cinnarizine and naftifine Naftifine, 15 an antifungal drug, can also be prepared in this way; 12 particularly, cinnamyl alcohol was treated with N-methyl-1-(naphthalen-1-yl)methanamine (4) to yield naftifine in 61% yield (Scheme 2). Each of these cases highlights a beneficial aspect of C1 and other iron hydride transfer catalysts in that the starting styryl olefin is not reduced under the conditions. 16 In many cases, ruthenium-and iridium-based catalysts will transfer hydrogen to alkenes in addition to imines, resulting in reduced efficiency of alcohol conversion and overreduction of the starting materials.
Piribedil (8) is a dopamine receptor agonist that is used in the treatment of Parkinson's disease and depression. 17 As a representative example of a larger class of pharmaceutically relevant N-arylpiperazines, 18 synthesis of piribedil by hydrogen-borrowing has been widely explored with different catalytic systems (Scheme 3).
In 2007, Williams and co-workers utilized [Ru(p-cymene)Cl2]2 to couple commercially available 1-(2-pyrimidyl)piperazine with piperonyl alcohol (7) to furnish piribedil in 87% yield. 8y This was an extension of their hydrogen borrowing methodology to couple various secondary amines with primary alcohols to obtain tertiary amines in the presence of [Ru(p-cymene)Cl2]2 and dppf. The yield increased from 87% to 98% when Ramalingam and coworkers replaced [Ru(p-cymene)Cl2]2 with a supported ruthenium catalyst that was prepared from [Ru(p-cymene)Cl2]2 and a commercially available, polystyrene supported phosphine ligand (10) in 1:6 ratio (C2, Scheme 3). 8j This ratio was crucial to obtain efficient catalytic activity and lower ruthenium leaching. In addition, the catalyst also showed comparable yields (96% and 97%) in two subsequent uses after its recovery from the initial mixture. Operational simplicity and easy recycling of this heterogenous catalyst enabled the authors to apply it in a packed bed reactor to scale up N-alkylation of piperidine under continuous flow. In 2014, Nandan's group employed an inexpensive W4 Raney nickel catalyst for the same transformation to yield piribedil in 85% yield. 19 This was an extension of their methodology utilized in the synthesis of pyrilamine. In addition, Feringa and co-workers reported piribedil synthesis using Knölker's complex in 54% yield. 20 Their methodology consists of a base free, one pot synthesis in a green solvent (cyclopentyl methyl ether, CPME), which apparently stabilizes key iron intermediates and facilitates imine reduction compared to other solvents. Finally, Cui and co-workers utilized NiCuFeOx catalyst to produce piribedil in 93% yield. 21 Pyrilamine (mepyramine, 15) is a first-generation antihistamine that blocks the H1 receptor. 22 Nandan and co-workers screened different grades of Raney nickel (W4, T4, and W7) and achieved selective monoalkylation of amines (e.g. 13) with W4 Raney nickel at 1:4 moles of amine to alcohol in xylene at reflux. This was demonstrated by producing pyrilamine as shown in Scheme 4. 19 As the first step of the route, N-(2-(dimethylamino)ethyl)pyridine-2-amine (13) was synthesized by a microwave assisted nucleophilic substitution reaction; the product was then coupled with 4-methoxy benzyl alcohol 14 to yield pyrilamine in 82% yield.
OH + HN N Ph Ph N N Ph Ph 3: Cinnarizine (62%) C1 (10 mol%) Me3NO (20 mol%), toluene,130 o C, 36h OH + N 5: Naftifine (61%) C1 (10 mol%) Me3NO (20 mol%), toluene,130 o C, 24h H N Fe CO OC CO O TMS TMS 1 2 1 4 N N N NH + O O OH N N N N O O 8: Piribedil 6, x equiv 7, y equiv + O P Ph Ph PS [Ru(p-cymene)Cl2]2 Toluene 110 o C, 3 h PS = polystyrene 9, 1 equiv 10, 6 equiv A. Synthesis of piribedil B. Preparation of catalyst C2 Williams et al. x:y = 1:1, [Ru(p-cymene)Cl2]2 (1.25 mol%), dppf (2.5 mol%), molecular sieves, toluene, reflux, 24 h, 87% yield Ramalingam et al. x:y = 1.0:1.2, C2 (5 mol%), toluene, 140 o C, 48 h, 98% yield Nandan et al. x:y = 1:4, Raney Ni (31 mg/ 1 mmol alcohol), xylene, reflux, 24 h, 85% yield Feringa et al. x:y = 1:4, C1 (5 mol%), Me3NO (10 mol%), CPME, 130 o C, 42 h, 54% yield Shi et al. x:y = 1:1, NiCuFeOx (50 mg/1 mmol alcohol), xylene, reflux, 24 h, 93% yield C2 polystyrene O P Ph Ph O P Ph Ph O P Ph Ph [Ru(p-cymene)Cl2]2 +
Scheme 4 Synthesis of pyrilamine While it's not an API, fluorescent saccharide sensor 18 was prepared by applying alcohol N-alkylation (Scheme 5) with commonly-incorporated ruthenium precursor 9 and is included here to illustrate the compatibility of 16's aryl boronic ester with hydrogen borrowing conditions. 23 Williams and co-workers produced 18 in 84% yield by a [Ru(p-cymene)Cl2]2 catalyzed coupling of methyl substituted secondary amine with a boronic ester, while the traditional reductive amination yielded the unprotected boronic acid product in 54% yield. 24 Thus, this example highlights both the compatibility of an arylboronic ester with a hydrogen borrowing catalyst and shows a significant yield advantage over the traditional reductive amination sequence.
Scheme 5 Synthesis of a saccharide sensor 18 Tigan (or trimethobenzamide, 21) is an antiemetic drug used to treat nausea and vomiting related to surgery or stomach flu. 25 A structurally similar drug, itopride (22), is an acetylcholine esterase inhibitor and a dopamine D2 receptor antagonist. 26 It is a medication for functional dyspepsia and other gastrointestinal conditions. In 2018, Banerjee and co-workers extended their nickel catalyzed phosphine free direct N-alkylation of amides with alcohols to synthesize tigan and itopride. 27 Compared to amines, N-alkylation of amides is challenging due to their weak nucleophilicity. The authors screened different nickel catalysts with oxidation states ranging from nickel(0) to nickel(II) (NiCl2, NiBr2, NiCl2-dme, Ni(acac)2, and Ni(cod)2) to find a system to catalyze coupling of model substrates benzyl alcohol and benzamide. They further screened different nitrogen ligands with variable electronic nature and a NiBr2-1,10-phenanthroline system was found for the selective formation of secondary amides. These conditions tolerated other challenging groups like nitriles, allylic ethers, and alkenes; but nitro groups, carboxylic acids, esters and alkynes were not successful. The optimized conditions generated tigan and itopride in 80% and 74% isolated yield, respectively (Scheme 6).
Scheme 6 Synthesis of tigan and itopride Catalytic hydrogen borrowing has excellent tolerance for dense functionalization, including strained rings, and many aryl halides. PF-03463275 (26) is a glycine transporter type 1 (GlyT1) inhibitor that has therapeutic potential against schizophrenia. 28 Process chemists from Pfizer Pharmaceutical Science demonstrated the first kilogram-scale application of hydrogen borrowing as a key step in the synthesis of PF-03463275. 29 Prior to hydrogen borrowing, these investigators tried to implement a two step oxidation/reductive amination sequence (Scheme 7B) to access the intermediate 25. Parikh-Doering oxidation generated aldehyde 23' from alcohol 23, which was not isolated due to stability and water solubility. Imine 25' was formed by reacting aldehyde 23' with amine 24 and was then reduced to 25 by sodium borohydride. Followed by a lengthy work up, intermediate 25 was crystallized as dihydrochloride salt in 30-45% yield. By-products such as dialkylated 25 and N-methylated 24 and 25 were identified, leading to significant drop in yield. The requirement for a new, more efficient process to deliver intermediate 25 led the team to optimize Yamaguchi's conditions for the N-alkylation of primary benzylic amines with primary alcohols using [Cp*IrCl2]2. 9w Despite a successful pilot study, executing this reaction on scale faced challenges of residual iridium that didn't meet API standard and incomplete conversion, as the formation of inorganic precipitates stalls the reaction. While modification of the filtration procedure resulted in low level of residual iridium, utilization of a sealed, Hastelloy pressure reactor helped to achieve full conversion. It is noteworthy that the coupling of alcohol 23 and amine 24 using less than 0.05 mol% of the catalyst generated drug intermediate 25 in 4.8 kg scale (Scheme 7A
). In addition, this one pot synthesis replaces a traditional 4 step approach to access 25. The Pfizer studies on the effect of solvent and base revealed that water and tertiary amine base are critical in achieving efficient and robust catalyst performance.
Scheme 7 Scale-up preparation of pharmaceutical intermediate 26 The case of Scheme 7 and many to follow highlight the utility of iridium in many of the more useful hydrogen borrowing catalysts. Cost and sustainability of iridium are both important considerations when manufacturing on scale, especially whereas, unlike other precious metals used in catalysis, no US vendor currently purchases and reprocesses iridium waste. To address this issue, we recently reported a convenient and scalable route to recover and recycle iridium from mixed catalyst waste. 30 Hydrogen borrowing reactions involving sulfur-containing amines are not abundant in literature, as strong coordination of sulfur can lead to catalytically inactive species. Quetiapine (29), a sulfur containing dibenzothiazepine derivative, is an atypical anti-psychotic drug used to treat schizophrenia, manic episodes, and depressive disorders in combination with other antidepressants. 31 To address its synthesis, Xu and coworkers screened different noble metal catalysts for the coupling of 25 (76%) 26 PF-03463275 4.8 kg H H H 23 24 23 SO3.Pyr DMSO, Et3N N H H H Me O N N H H Me Cl F H 23' 25' 25 (30-45%) 24 1. NaBH4, MeOH, workup, then 2. HCl, 2-propanol A. Hydrogen borrowing B. Reductive amination Synthesis Review / Short Review Template for SYNTHESIS Thieme thiomorpholine and benzyl alcohol and discovered a base free RuCl2(H2O)(CO)(PPh3)2 catalyzed reaction to obtain desired product in 95% yield. The authors applied this method to access quetiapine from amine 27 and diethylene glycol (28) in 90% yield (Scheme 8). 32 This green reaction replaces a conventional chlorination of diethylene glycol to 2-(2-chloroethoxy)ethanol followed by its nucleophilic substitution reaction with amine 27 to produce quetiapine. 33 Scheme 8 Synthesis of quetiapine Pheniramine ( 32) is a first-generation antihistamine which is used to treat allergic conditions such as urticaria or hay fever. 34 In 2013, Cui and coworkers designed an air and moisture stable NiCuFeOx catalyst for the alkylation of ammonia and amines with various alcohols and diols. 21 Here, they extended the methodology to prepare piribedil (Scheme 3) and pheniramine (Scheme 9), demonstrating alkylation of a volatile amine with an earth-abundant catalyst. Similar to other heterogenous catalysts, utilization of NiCuFeOx eliminated the need for organic ligands and bases. Furthermore, the magnetic property of this catalyst resulted in its easy separation and reuse for several runs without apparent deactivation.
Meclizine (34) and buclizine (35) are H1 antihistamines that are used to treat nausea, vomiting, and dizziness associated with motion sickness. Notably, meclizine is among the top 200 prescribed drugs in the USA. 35 Traditional synthesis of these drugs with a 1-diphenylmethyl piperazine fragment involves the halogenation of the alcohol functional group followed by a nucleophilic substitution with the amine which generates concerns regarding safety and cumbersome waste disposal in large scale synthesis. 36 In 2023, scalable syntheses of meclizine and buclizine were reported, incorporating an iridium catalyzed hydrogen borrowing reaction (Scheme 10). 37 The work highlights a tradeoff between yield and PMI value: even though buclizine was obtained in 95% yield with no residual iridium content by silica column chromatography, the PMI value increased significantly to 1497.6 from 3.1 prior to purification. Therefore, the authors employed an efficient salt precipitation strategy to produce buclizine hydrochloride salt in 65% yield with a low residual iridium (23 ppm) and an overall PMI of 50. Similarly, the hydrochloride salt of meclizine was obtained in 60% yield with 13 ppm of residual iridium and 59.3 PMI.
Scheme 10 Synthesis of meclizine and buclizine Two case studies have been reported in which traditional alkylation conditions were directly compared with catalytic hydrogen borrowing reactions by a pharmaceutical process group. For example in 2015, Newton and co-workers at AstraZeneca conducted a survey of hydrogen borrowing strategies to synthesize various pharmaceutically relevant intermediates. 10 They focused primarily on two catalytic systems: (1) a system developed by the Williams group 8u (2.5 mol% [Ru(p-cymene)Cl2]2/ 5 mol% DPEphos/ 1 M toluene) and (2) a system from Fujita and Yamaguchi 9q (2.5 mol% [Cp*IrCl2]2/ 5 mol% NaHCO3/ 10 M toluene). In the first example, they showed an alternate pathway to access piperazinyl alcohol 37, an important intermediate in the synthesis of a potent SRC kinase inhibitor (39, Scheme 11) in 89% yield by hydrogen borrowing with a [(Cp)RuCl(PPh3)2] catalyst. Although the previous reductive amination route to this amino alcohol yielded the methylated compound in 93% yield, excess formaldehyde, a potential carcinogen, had to be removed by converting it into volatile diethylmethylamine by treating with diethyl amine. Thus, hydrogen borrowing established a simpler one pot synthesis of 37 with comparable yield and a trouble-free, distillation-based isolation. Moreover, self-condensation of hydroxyl bearing piperazine 36 was not observed under these catalytic conditions. Scheme 11 Role of amino alcohol 37 in the synthesis of API 39 Another example from Newton and co-workers was aniline derivative 43, an intermediate in the synthesis of an antihepatitis API 46. The previous synthetic route to 43 involved alkylation of sulfonamide 40 with p-nitrobenzyl bromide (41), followed by reduction of the nitro group (Scheme 12A). 38 Alternatively, [Ru(p-cymene)Cl2]2 can be employed to produce compound 45 from piperazine TFA salt 40 and Boc protected paminobenzyl alcohol (44, Scheme 12B); note that the TFA salt was compatible with the hydrogen borrowing conditions and afforded 45 in 92% yield. Acidic cleavage of 45 yielded API intermediate 43 in in 89% yield.
While stereochemistry of epimeric secondary alcohols is typically ablated in hydrogen borrowing because of the intermediate ketone, some conditions preserve chirality of amine stereocenters, thus enabling enantiospecific amination. Other approaches exploit the ablation of chirality at secondary alcohols to enable a chiral catalyst or auxiliary to introduce chirality into an API through the hydrogen borrowing sequence. Some examples of these follow.
The hydrogen borrowing synthesis of cinacalcet hydrochloride (brand name Sensipar, 49-HCl) illustrates an enantiospecific hydrogen borrowing amination. Sensipar is used to treat hyperparathyroidism and hypercalcemia. 39 It is the first FDA approved drug in the class of calcimimetics. Several methods have been reported for the preparation of Sensipar: the most common strategy is the condensation of 1(R)-(1naphthyl)ethylamine (47) with 3-(3-(trifluromethyl)phenyl)propionaldehyde to generate the corresponding imine, followed by its reduction with a boronbased reducing agents such as NaBH4, NaBH3CN, or NaBH(OAc)3. 40 Large scale production of cinacalcet is achieved using an iridium (C3, Scheme 10) catalyzed hydrogen borrowing reaction from 1(R)-(1-naphthyl)ethylamine and 3-(3-(trifluromethyl)phenyl)-1-propanol (48) with a reaction PMI value of 1.2 and a reaction STY (space-time yield) of 29.8 g/L-h (Scheme 13). 37
Unfortunately, these investigators were unable to convert the batch protocol of Scheme 13 into a reasonable continuous flow process due to the long reaction time required for hydrogen borrowing. Efforts to increase the reaction rate by increasing the temperature significantly dropped the yield due to the decomposition of the catalyst. However, this methodology outperformed other patented procedures by generating 71 g of cinacalcet (enough to produce 2600 tablets of a 30 mg dose) in a single batch using simple and compact reaction setup as well as under solventless condition with an improved PMI.
While some academic labs have introduced methods for enantioselective hydrogen borrowing amination, 41 none has yet appeared in an API synthesis. Several pharmaceutically relevant examples have appeared, however, that leverage a chiral auxiliary strategy to introduce chirality through a highly selective hydrogen borrowing amination. Three such examples follow. Each features iridium catalysis, which again underscores the importance of its stewardship and recycling. 30 Diastereoselective amination of alcohols with chiral tertbutanesulfinamides has been developed to access secondary sulfinamides in high yield. For example, rivastigmine 42 (56, brand name Exelon) is an acetylcholinesterase inhibitor, used to treat dementia associated with Alzheimer's or Parkinson disease. Xia and coworkers synthesized the intermediate 52 in the formation of (S)-rivastigmine (Scheme 14). 43 Coupling of racemic alcohol 50 and (S)-tert-butanesulfinamide (51) with C3 yielded the desired alkylated compound (52) in high yield with excellent diastereoselectivity. Next, an acidic desulfination of 52 produced an α-chiral amine (S)-53 with 99% ee. This was doubly methylated to compound 54 using excess formic acid and formaldehyde, then, deprotection of the aryl methyl ether and carbamoylation with the N-ethyl-N-methylcarbamoylchloride yielded (S)-rivastigmine (56) in 64% overall yield. Scheme 14 Synthesis of (S)-rivastigmine (56) The API NPS R-568 (N-(3-[2-chlorophenyl]propyl)-(R)-αmethyl-3-methoxybenzylamine) is a type II calcimimetic compound that inhibits the secretion of parathyroid hormone by binding to the parathyroid Ca 2+ receptor. 44 The intermediate 52' was synthesized using the same iridium (C3) catalyzed diastereoselective N-alkylation as before, this time converting racemic alcohol and (R)-tert-butanesulfinamide to 52' (Scheme 15). 43 Subsequently, removal of sulfinyl group followed by reductive amination with 57 afforded NPS R-568 in 63% overall yield with 99% ee.
Nitrogen heterocycles appear ubiquitously in APIs. Thus, several groups have used hydrogen borrowing methods in intramolecular cases and tandem sequences to enable cyclization of heterocycles, in some cases with the installation of stereochemistry. Several such cases of API and natural product synthesis are outlined here.
Noranabasamine ( 59) is an amphibian alkaloid which is isolated from a Colombian poison dart frog Phyllobates terribilis. 45 It has gained significant attention due to its resemblance to the plant derived piperidine alkaloids 60 and 61 (Scheme 16), which show therapeutic effect on nicotinic acetylcholine receptor. 46 Trudell and co-workers have reported an enantioselective synthesis of both (R) and (S) enantiomers of noranabasamine in three steps with more than 30% overall yield and > 80% ee. 47
The first step, the synthesis of the 2-substituted piperidine scaffold, incorporated an iridium catalyzed diastereoselective Nheterocyclization of (S)-phenylethylamine with diols, as reported by Yamaguchi and co-workers in 2004. 9s This reaction proceeded in high yield with both (R) and (S)-phenylethylamine to afford the corresponding diastereomer of 64 in excellent selectivity.
Thereafter, the hydrogenolysis of the N-phenylethyl auxiliary of 64 followed by POCl3 treatment yielded the corresponding antipode of 65. Finally, a Suzuki coupling of 65 with 3pyridineboronic acid produced the respective enantiomers of noranabasamine from the corresponding a-phenethyl amines 63 in good enantioselectivity. 48 Formation of 64 illustrates piperidine synthesis through the double amination of a single nitrogen atom. Our lab extended this strategy by building an intervening Pictet-Spengler reaction into an analogous double amination sequence, enabling a cascade approach to indole alkaloids. For example, harmicine is a natural product with antileishmanial and antinociceptive activity. 49 We assembled this tetracyclic alkaloid from 1,4-butanediol and tryptamine by a ruthenium catalyzed one-pot hydrogen-borrowing/Pictet-Spengler reaction. 50 The tandem sequence (Scheme 17) begins with the condensation of tryptamine (66) with the aldehyde generated from the in-situ oxidation of one of the alcohols in diol 67 to generate compound 69, which is further reduced to compound 70 by a ruthenium hydride. The challenge of engineering the tandem sequence was to intercept iminium 71 prior to its reduction by the system's intermediate ruthenium hydride. Catalyst C4 was designed for two unique properties that it introduced into the hydrogen borrowing literature: it is one of the only catalysts that is not base dependent, here working in the presence of TFA, which is vital to enabling the acid-dependent Pictet-Spengler reaction, and it enables reversible alcohol redox faster than imine formation or reduction, causing kinetic, rather than thermodynamic, selectivity for alkylation of poly amine systems. 51 The catalyst realizes these properties through cooperation of multiple metals in an active catalytic cluster. 52 The harmicine tandem sequence thus proceeds with an intramolecular cyclization of 71, which yields harmicine ( 68) in 50% yield. The majority balance of tryptamine is isolated as its TFA amide. A competing catalyst has also been reported. 53 Scheme 17 Synthesis of harmicine from tryptamine and 1,4-butanediol
Catalyst C4 also enabled the first examples of tandem cyclization of diamines and diols. 54 This we demonstrated in the synthesis of cyclizine, 55 an essential drug on the FDA list. It is an antiemetic used to treat nausea and vomiting due to motion sickness. Further, homochlorcyclizine is an antihistamine that is marketed in Japan. 56 Each of these diazacycles can be synthesized by consecutive, in situ hydrogen borrowing reactions between diamines and diols (Scheme 18A). Curiously, formation of diazapanes with C4 is much more efficient for the cyclization of propyl diamines and ethylene glycol than from ethylene diamines and propylene glycol. For example, ethylene glycol will cyclize onto N,N'-dibenzyl-1,3diaminopropane (78) in 86% yield, while propylene diol and di-N-benzylethylene diamine form the same product (76) in 78% yield. We rationalize this by observing that cyclization reactions of ethylene glycol require only one hydrogen borrowing cycle, owing to the ability to isomerize the intermediate iminium to generate the second requisite aldehyde (Scheme 19). 54
A further uniqueness of C4 is that other hydrogen borrowing catalysts tend to deactivate, apparently by diamine chelation, in the presence of 1,2-diamines in our hands. Catalytic poisoning studies with stoichiometric amount of C4 and diamines showed that C4 maintains its reactivity by forming a catalytically active complex by chelation in the case of substituted diamines other catalysts are not.
Cyclizine can also be prepared by methylating diphenylmethyl piperazine (Scheme 18B). 37 Good PMI values were achieved by precipitating the amine as its HCl salt with low iridium content (30 ppm) in the final API which comply with API regulatory guidelines.
While there are far more C-N bond forming reactions than can be concisely summarized here, we will highlight a few common routes that compete with hydrogen borrowing in API synthesis, providing citation to work in which they are reviewed.
An SN2 reaction between an amine and alkyl halide is a classical method for producing substituted amines (Scheme 20), 2 most frequently utilizing bromide and iodide electrophiles. This simple method is an efficient way to generate tertiary and quaternary amines, but the classical method has a classical problem: primary or secondary amines are not readily prepared by alkylation because of competing over alkylation. Secondary amines are characteristically more nucleophilic than the primary amine, so direct alkylation generally leads to quaternary ammonium salts. The cost of purification resulting from this selectivity issue make the amination of halides as an unfavorable reaction for amine manufacturing.
As hydrogen borrowing reactions are substrate dependent, not all SN2 reactions can be replaced with a hydrogen borrowing route using a currently known catalyst. For example, ropivacaine (81), 57 an anesthetic and acute pain reliever, can be prepared by the alkylation of piperidine amine 79 with propyl bromide (80, Scheme 20B). 58 Newton and coworkers attempted to replace this transformation with hydrogen borrowing using [Ru(pcymene)Cl2]2 or [Cp*IrCl2]2 (Scheme 20C). 10 Even though alcohol oxidation occurs in both cases, the iminium ion formed by the condensation of amine 79 with propanal is captured by the pendant amide, leading to aminals 83 (major) and 83' (minor), which were resistant to ring opening. Thus, hydrogen borrowing reactions may not be suitable for substrates with a nucleophilic functional group proximate to the intermediate iminium ion without a catalyst that reduces the imine faster than the undesired nucleophilic addition.
Scheme 20 General scheme for alkylation of amines with halides and synthesis of ropivacaine
Reductive amination is indeed a powerful reaction in the construction of C-N bonds. 3 Selectivity and operational simplicity make it the most popular method for producing commercial drug substances such as imatinib (anticancer), oseltamivir (antibiotic), sitagliptin (antidiabetic), etc. 59 The main advantage of this method is the selectivity against overalkylation compared to an SN2 reaction, where mixture of mono, di, tri, and tetra alkylated compounds are formed. Reductive amination consists of two steps (Scheme 21): (1) a condensation reaction between an amine and a carbonyl compound to form an imine, and (2) reduction of the imine to an amine by a metal hydride such as NaBH4. This contrasts hydrogen borrowing by the use of stoichiometric oxidizing and metal hydride agents and by fully obviating any opportunity for over alkylation. In addition to aldehydes and ketones, carbonyl precursors such as carboxylic acids, nitriles, and organic carbonates have been employed. Amine precursors like nitro or nitroso compounds have been utilized as nucleophilic partners. Development of transition metal catalyzed reductive amination using molecular hydrogen as the reducing agent was a milestone in bulk scale chemical production and asymmetric synthesis. In 2020, Irrgang and Chempe published a comprehensive review focusing on this. 60 Template for SYNTHESIS Thieme Scheme 21 Reductive amination
Aryl amines can be prepared by coupling amines with aryl halides. Buchwald-Hartwig amination, 4a-b copper-catalyzed Ullman type reactions, 4c and Petasis reaction are the common named reactions in this category.
Buchwald-Hartwig amination (Scheme 22) is a palladium catalyzed cross coupling of amines with aryl/vinyl/heteroaryl halides or pseudohalides. Due to the ubiquity of the C-N bond in biologically active compounds and natural products, this method has contributed significantly to the production of small molecule drugs since its discovery.
61 Various generations of palladium catalyst systems have been developed with different phosphine ligands such as Xantphos, dppf, BINAP, trialkyl phosphines, and N-heterocyclic carbenes. The choice of palladium source, ligand system, base, and reaction conditions (e.g. solvent and temperature) are highly substrate dependent. Compared to the classical methods like nucleophilic substitution and reductive amination, this palladium catalyzed cross coupling provides broad substrate scope with a variety of amines (primary, secondary, electron deficient, and heterocyclic). However, scope of this reaction is limited to arylation of amines with very few examples reported for alkylation. 62 Scheme 22 Buchwald-Hartwig amination
Ullman condensation is a copper catalyzed cross coupling of nucleophiles (amines, alcohols, and thiols) with aryl halides (Scheme 23). Even though this reaction was used in the synthesis of important intermediates in pharmaceutical and polymer industries, it has been substantially displaced by more modern Buchwald-Hartwig reactions due to its limited substrate scope and forcing conditions. Traditional Ullman-type coupling reactions require high temperature, aryl halides with electron withdrawing groups, and activated copper powder. However, scope of such copper catalyzed coupling reactions is increasing recently with the introduction of soluble copper catalysts, and simple, inexpensive ligands that compete with the more complex and expensive phosphine ligands seen commonly in Buchwald-Hartwig reactions. 4c, 63
The Petasis boron-Mannich reaction or Petasis reaction is a multi-component reaction of an amine, carbonyl compound, and boronic acid that produces a substituted amine (Scheme 24). As a mild and selective synthetic strategy, it is employed in the formation of β-amino alcohols, amino acids, and aminophenols. A wide variety of carbonyl derivatives (α-hydroxy aldehydes, salicylaldehyde and derivatives, lactols, glyoxylic acid and derivatives, protected α-amino aldehydes, α-imino amides, formaldehyde, benzaldehyde), 64 amine substrates (secondary amines, tertiary aromatic amines, 65 hydrazines, 66 hydroxyl amines, 67 sulfonamides, 67 indoles 68 ), and boronic acids and esters have been reported. As a powerful reaction to make highly functionalized amine derivatives with good diastereoselectivity and enantioselectivity, it is utilized in the total synthesis of natural products like polyhydroxy alkaloids, loline alkaloids, and sialic acids. 64 Scheme 24 Multi-component Petasis reaction
Hydroamination is the addition of hydrogen and nitrogen group across the C-C multiple bond of an alkene or alkyne (Scheme 25). 5 This atom economical and green reaction contributes to the synthesis of substituted amines via intermolecular addition, and to the preparation of heterocycles and alkaloids
69 in intramolecular implementations. While thermodynamically prohibitive as a [2+2] cycloaddition, the process became feasible with the development of catalysts that open new, stepwise mechanisms. Regioselectivity is challenge of hydroamination: the possibility of both Markovnikov and ani-Markovnikov additions must be controlled by the catalyst if directing effects in the substrate do not prevail. 70 A broad range of catalysts including acids, bases, main group elements, non-noble metals, rare-earth metals, and transition metals are reported, 71 even photoredox conditions have emerged, 72 yet research and development in this area remains active, particularly toward the discovery of enantioselective catalysts. Scheme 25 Hydroamination of alkene 3.5 Chan-Lam Reaction Chan-Lam coupling is a widely used reaction to make carboncarbon and carbon-heteroatom bonds, especially as in the arylation of amines. The reaction was discovered by Chan, Evans, and Lam in 1998, 73 and efficiently couples aryl boronic acids with different nucleophiles containing N-H, O-H, S-H or P-H groups in the presence of a copper or nickel catalyst (Scheme 26). 74 In addition to amines, other nitrogen nucleophiles such as amides, 75 sulfonimidamides, 76 phosphonamides, 77 and azides 78 can be employed. Compared to other C-N bond forming coupling + R1, R2, R3, R4 = Aryl or vinyl R3 H O + B OH HO R4 N H R1 R2 N R2 R1 R4 R3 R3 H N R2 R1 B OH HO R4 OH Synthesis Review / Short Review Template for SYNTHESIS Thieme reactions, the Chan-Lam method benefits from mild reaction conditions, lower toxicity, and a lower catalyst cost than competing palladium-based or hydrogen borrowing reactions.
Even though Chan-Lam reactions are used mostly with aromatic amines and arylboronic acids, coupling of primary aliphatic amines 79 and cyclic secondary amines 80 with boronic acids/esters are also reported. In addition, N-benzylation is achieved by coupling benzyl boronic acid with N-methyl substituted amines. 81 Chan-Lam reactions are employed in the efficient synthesis of an anti-epileptic drug 82 and compounds having anti-viral and anti-cancer activities. 83 Compared to the hydrogen borrowing method, the Chan-Lam reaction has limited substrate scope in its amine component.
Scheme 26 Chan-Lam reaction
The Mitsunobu reaction couples primary and secondary alcohols with pronucleophiles ((thio)carboxylic acids, (thio)phenols, sulfonamides, and imides) in the presence of dialkyl azodicarboxylate, and a trialkyl or triaryl phosphine (Scheme 27A). 84 Generally, the pKa of the pronucleophile should be around 11 or less in order to avoid alkylation of the diazo reagent. However, alkylation of amines using primary benzylic and nonbenzylic alcohols are reported under Mitsunobu conditions using a highly nucleophilic N-heterocyclic phosphine 85 Synthesis of simple drugs such as cinnarizine (Scheme 27B) and piribedil are achieved utilizing this methodology; 82 contrast this route to cinnarizine (74%) to that of Scheme 2, in which the same transformation is executed in 62% yield by iron catalysis and water as the sole waste product.
This reaction benefits from mild reaction conditions and the absence of metallic impurities necessary for hydrogen borrowing and metal catalyzed coupling reactions. Owing to its pKa restriction, the Mitsunobu approach lacks broad substrate scope on both alcohol and amine partners. Further, removal and disposal of by-products such as phosphine oxide and hydrazine derivatives make the purification process cumbersome.
The prevalence of substituted amines and nitrogen rich heterocycles in dyes, agrochemicals, and detergents increase the appeal of hydrogen borrowing reactions in process chemistry. Currently, SN2 reactions between amine and alkylating agents, and reductive amination contribute much of the N-substitution reactions in industry. Alkyl halide waste, the additional step involved in halide construction, poor chemoselectivity, and tedious purification procedures make such SN2 reactions a target for modern reaction development. Similarly, reductive amination requires a stoichiometric reducing agent, construction and intermediacy of a potentially fragile carbonyl compound, and purification of an amine product away from stoichiometric waste. However, redox neutral hydrogen borrowing reactions are green, atom economic, selective and efficient, with water as the sole byproduct. Several homogenous and heterogenous catalysts have been reported in the literature to couple various nitrogen nucleophiles with alcohols to produce pharmaceutical intermediates and APIs. While the viability of hydrogen borrowing in manufacturing applications depends on addressing some challenges of this strategy such as catalyst poisoning, high catalyst loading, solvent toxicity, residual metal content in API products, and elevated reaction times and temperatures, it is promising that the recent process development studies showed the utility of catalytic hydrogen borrowing amination in scalable synthesis of some APIs in neat or green solvent conditions with good PMI values and low catalyst loadings. This is a stepping stone for other process chemists to explore emerging hydrogen borrowing approaches in drug development.