Large-Scale Applications of Amide Coupling Reagents for the

Review pubs.acs.org/OPRD

Large-Scale Applications of Amide Coupling Reagents for the Synthesis of Pharmaceuticals Joshua R. Dunetz,*,† Javier Magano,*,‡ and Gerald A. Weisenburger*,‡ †

Process Chemistry, Gilead Sciences, 333 Lakeside Drive, Foster City, California 94404, United States Chemical Research & Development, Pfizer Worldwide Research & Development, Eastern Point Road, Groton, Connecticut 06340, United States

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‡

ABSTRACT: This review showcases various coupling reagents which have been implemented specifically for large-scale amide synthesis via the condensation of an acid and amine, while highlighting the benefits and drawbacks of each reagent on an industrial scale.

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CONTENTS

1. Introduction 2. Reagents for Amide Coupling 2.1. Coupling via Acid Chloride 2.2. Coupling via Acid Anhydride 2.2.1. Carboxylic/Carbonic Acid Anhydrides 2.2.2. Sulfonate-Based Mixed Anhydrides 2.2.3. Phosphorus-Based Mixed Anhydrides 2.2.4. CDI 2.3. Coupling via Activated Ester 2.3.1. Carbodiimides 2.3.2. Phosphonium Salts 2.3.3. Guanidinium and Uronium Salts 2.3.4. Triazine-Based Coupling Reagents 2.4. Coupling via Boron Species 3. Other Methods for Amide Bond Formation 3.1. Synthesis of Amides from Esters 3.2. Synthesis of Amides via Transamidation 3.3. Synthesis of Amides Catalyzed by Brö nsted Acids 4. Case Studies 4.1. Coupling via Acid Chloride 4.1.1. Thionyl Chloride 4.1.2. Oxalyl Chloride 4.1.3. Phosphorus Oxychloride 4.1.4. Commercial Vilsmeier Reagent 4.2. Coupling via Carboxylic or Carbonic Acid Mixed Anhydride 4.2.1. Acetic Anhydride 4.2.2. Pivaloyl Chloride (PivCl) 4.2.3. Ethyl Chloroformate (ECF) 4.2.4. Isobutyl Chloroformate (IBCF) 4.2.5. Boc Anhydride 4.2.6. EEDQ 4.3. Coupling via Sulfonate-Based Mixed Anhydride 4.3.1. Methanesulfonyl Chloride (MsCl) 4.3.2. p-Toluenesulfonyl Chloride (TsCl) 4.4. Coupling via Phosphorus-Based Mixed Anhydride

© 2015 American Chemical Society

4.4.1. n-Propanephosphonic Acid Anhydride (T3P) 4.4.2. Ethylmethylphosphinic Anhydride (EMPA) 4.5. Coupling via CDI 4.6. Coupling via Carbodiimide 4.6.1. DCC 4.6.2. DIC 4.6.3. EDC 4.7. Coupling via Phosphonium Salt 4.7.1. BOP 4.8. Coupling via Guanidinium and Uronium Salt 4.8.1. HBTU 4.8.2. HATU 4.8.3. TBTU 4.8.4. TPTU 4.8.5. TOTU 4.9. Coupling via Triazine Reagent 4.9.1. Cyanuric Chloride 4.9.2. CDMT 4.9.3. DMTMM 4.10. Coupling via Boron Reagent 4.10.1. Boric Acid 4.10.2. 3-Nitrophenylboronic Acid 5. Conclusions Author Information Corresponding Authors Notes Abbreviations References

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1. INTRODUCTION Many reviews of amide bond formation have already been written.1 This manuscript differentiates itself by evaluating coupling reagents used in the large-scale condensation of an acid and amine for the synthesis of drug candidates, while

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Received: September 20, 2014 Published: November 15, 2015 140

DOI: 10.1021/op500305s Org. Process Res. Dev. 2016, 20, 140−177

Organic Process Research & Development

Review

Chart 1. Found Number of References Included in This Review for Each Coupling Reagent for Amide Bond Formation above 100 mmol Scale through June 2015

the peer-reviewed journals; while the patent literature contains many instances of amide coupling, the scientific details within these legal documents are often limited. Finally, the references at the end of this review are labeled to provide quick access to lists of large-scale examples for each coupling reagent.

highlighting the benefits and drawbacks of each reagent on plant scale. Amide bonds are very frequently incorporated into active pharmaceutical ingredients (API).2 In fact, amide bond formation is one of the most prevalent transformations in the pharmaceutical industry, accounting for 16% of all reactions carried out in medicinal chemistry laboratories.3 However, the ideal method for amide synthesis, i.e., the direct condensation of a carboxylic acid and an amine with the formation of one equivalent of water as the only byproduct,4 is not practical due to proton exchange between the coupling partners leading to an ammonium carboxylate salt. Only under forcing conditions (such as high temperature5 and microwave irradiation6) can this coupling take place, which makes it incompatible with the chemical complexity displayed by current drug candidates. As a result, acid activation is required to promote the coupling with an amine, and the development of safe and efficient processes for acid activation and amine condensation on industrial scale is of paramount importance. There are many considerations when selecting an amide coupling reagent for plant production. The ideal reagent is inexpensive, widely available, nontoxic, safe, simple to handle, easy to purge from reaction mixtures, and contributes only minimally to waste streams. Furthermore, the detection and purging of coupling byproducts to regulatory limits is high priority when performing the amidation near the end of a manufacturing route.7 Of course, not all coupling reagents perform equally well for a given pair of acid and amine substrates, and the aforementioned process considerations must be balanced against the need for amidation conditions that proceed with high yield and selectivity, excellent reproducibility, and in the case of substrates bearing stereocenters, low epimerization. The first half of this review introduces the various amide coupling reagents and compares the merits of each for largescale amidation. The second half of this review details case studies in which these reagents were applied in an industrial setting. As with our previous reviews,8 the referenced examples are limited to couplings which contain a detailed experimental procedure above 100 mmol scale, which spans laboratory to plant reactions on grams to hundreds of kilograms of substrate. This manuscript only covers examples which have appeared in

2. REAGENTS FOR AMIDE COUPLING Chart 1 describes the number of reports above 100 mmol scale found in the mainstream literature for each coupling reagent through June 2015. Based on the number of publications, the preferred methods for large-scale acid activation are (1) activated ester formation with carbodiimides (71 instances), with EDC and DCC as the top choices, (2) acid chloride formation (70 instances) with thionyl chloride and oxalyl chloride as the preferred reagents, and (3) CDI (38 instances). Other reagents that have received considerable attention are pivaloyl chloride (PivCl), isobutyl chloroformate (IBCF), and n-propanephosphonic acid anhydride (T3P) for the preparation of mixed anhydrides. 2.1. Coupling via Acid Chloride. Activation of a carboxylic acid as the corresponding acid chloride and subsequent reaction with an amine is one of the oldest approaches to amide bond formation.9 The high reactivity of acid chlorides toward amines generally leads to fast couplings which can be especially useful for sterically hindered substrates. However, epimerization via the ketene or azlactone is a potential problem if the acid contains an α-stereocenter. Several reagents have been employed on large scale for acid chloride preparation: thionyl chloride (SOCl2), oxalyl chloride ((COCl)2), phosphorus oxychloride (POCl3), and Vilsmeier reagent (Figure 1). SOCl2 and (COCl)2 are, by far, the two most widely employed reagents for acid chloride formation in

Figure 1. Structures of reagents for amide bond formation via acid chloride. 141



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Scheme 1. Mechanism of Acid Chloride Formation with SOCl2 Catalyzed by DMF

process chemistry. A drawback of these methods is that HCl is a byproduct of acid chloride generation, which can lead to incompatibility with acid-sensitive functional groups. With reagents such as thionyl chloride, oxalyl chloride, and phosphorus oxychloride, a small amount of DMF is typically added to serve as a catalyst for acid chloride formation. Scheme 1 details the mechanism for acid chloride formation via SOCl2 and catalytic DMF, which proceeds via Vilsmeier−Haack intermediate (Vilsmeier reagent10) and regenerates DMF together with the desired acid chloride.11 The Vilsmeier reagent is commercially available as a stable, free-flowing, crystalline solid which allows the purchasing chemist to bypass its preparation and the associated safety risks related to the handling of SOCl2 or (COCl)2 (vide infra). However, commercial Vilsmeier reagent is relatively expensive compared to alternatives for amide bond formation, which contributes to the limited use of this preformed reagent in process chemistry.12 The subsequent reaction of the acid chloride with an amine can be implemented under anhydrous conditions using an organic base, such as Et3N, i-Pr2NEt, or pyridine, to neutralize byproduct HCl. Despite their water sensitivity, acid chlorides can react with amines in the presence of an aqueous base (NaOH, NaHCO3, K2CO3, K3PO4) under Schotten−Baumann conditions. Thionyl chloride is the most common reagent in process chemistry for the conversion of a carboxylic acid to an acid chloride.13 One of the primary factors is cost, since the reagent is inexpensive and represents one of the most cost-efficient ways of preparing acid chlorides.14 However, one disadvantage of thionyl chloride is the potential formation of dimethylcarbamoyl chloride, a known carcinogen in animal models, when used in combination with DMF as catalyst.15 The mechanisms for the formation of this side product are shown in Scheme 2.16 Common solvents for acid chloride formation with SOCl2 include toluene, THF, n-heptane, MeCN, and DME. However, it is also possible to employ SOCl2 as both reactant and solvent. Upon reaction completion, excess thionyl chloride can be removed by distillation before isolating the acid chloride or telescoping the reaction mixture directly into the amidation. Oxalyl chloride has also been commonly employed in process chemistry for acid chloride generation.17 Advantages of this reagent relative to SOCl2 include: (1) its lower boiling point (61 °C versus 75 °C) which allows for easier removal of excess reagent via distillation, and (2) unlike the SOCl2/DMF combination, (COCl)2/DMF does not form dimethylcarbamoyl chloride.15 However, equivalents of CO2 and highly toxic CO are generated as byproducts, and adequate safety and engineering controls are required to accommodate the offgassing.

Scheme 2. Mechanisms for the Formation of Dimethylcarbamoyl Chloride

Acid chloride formation via (COCl)2 can be scaled in a number of solvents, such as toluene, THF, EtOAc, i-PrOAc, or MeCN. Upon reaction completion, distillation can remove excess oxalyl chloride; however, the acid chloride thus obtained is not usually isolated, but carried directly into the amide bond formation with the corresponding amine. Phosphorus oxychloride (phosphoryl chloride) has been rarely reported on large scale for carboxylic acid activation,18 although this reagent is readily available in bulk and represents a cost-effective alternative to SOCl2. No examples with phosphorus trichloride or phosphorus pentachloride for acid chloride generation on a large scale have been found in the peer-reviewed literature, despite the fact that these reagents are readily available in bulk and are very competitive in cost. Finally, amide bond formation through the acylation of commercially available acid chlorides is also common practice on large scale and circumvents the need for acid activation.19 On the other hand, commercially available acid bromides have seen a much more limited use,20 most likely due to the higher cost and far smaller number of choices. 2.2. Coupling via Acid Anhydride. 2.2.1. Carboxylic/ Carbonic Acid Anhydrides. Amide bond formation via mixed anhydride is one of the oldest approaches and only the acyl chloride and acyl azide methods predate it. Carbon-based mixed anhydrides can be subdivided into two categories depending on the type of activating reagent (Figure 2): 1. Mixed carboxylic acid anhydrides, which are formed with reagents such as acetic anhydride or pivaloyl chloride. There are two major drawbacks associated with carboxylic acid mixed anhydrides: (1) regiochemical control, which can be avoided by increasing the steric 142



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Figure 2. Reagents for amide coupling via mixed carboxylic and carbonic anhydrides.

Scheme 3. Amide Bond Formation via Acid Activation with EEDQ

Ethyl chloroformate (ECF) has been used as a coupling reagent on a large scale,19j,23 although less commonly than isobutyl chloroformate. The benefits of ethyl chloroformate include its low cost (less expensive than isobutyl chloroformate) and widespread availability. Although this reagent is highly toxic and more volatile than its isobutyl analog, its byproducts (EtOH and CO2) are relatively benign, and EtOH is typically easier to remove via aqueous extraction than the isobutanol byproduct of isobutyl chloroformate.23c The offgassing of byproduct CO2 requires that waste streams are properly quenched to avoid the buildup of pressure in sealed waste disposal containers. Isobutyl chloroformate (IBCF) is a fairly common coupling reagent for large-scale amide bond formations.13d,17d,19ah,24,25 This reagent is widely available in bulk quantities and inexpensive. Compared to ethyl chloroformate, the isobutyl reagent is less toxic, and its mixed anhydride shows greater selectivity in the reaction of the amine (due to the greater steric demand of isobutyl vs ethyl). Its byproducts, namely, isobutanol and CO2, are relatively innocuous, but as for ethyl chloroformate, IBCF must be properly quenched to avoid pressurization of drummed waste streams via the offgassing of CO2. Boc anhydride, or di-tert-butyl dicarbonate (Boc2O), is not a common acid-activating reagent for large-scale amide couplings.26 As a low-melting solid (23 °C), this reagent is more easily handled as a solution. Finally, EEDQ, or 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline, was first described as a reagent for amide couplings in 1968.27 The reagent converts a carboxylic acid to the same mixed anhydride expected from ethyl chloroformate activation (Scheme 3). EEDQ is similar to CDI and carbodiimides (vide infra) in that it mediates amide coupling without requiring additional base. This reagent is relatively inexpensive, widely available, and its coupling byproducts (quinoline, EtOH) can be purged by extraction into acidic aqueous media. Despite its longevity, only one example of EEDQ on large scale has been found in the peer-reviewed literature.28

bulk of the reagent that is used to form the mixed anhydride; (2) disproportionation to a mixture of the two possible symmetrical anhydrides. However, disproportionation can be avoided by forming the mixed anhydride immediately prior to reaction with the amine. 2. Mixed carbonic acid anhydrides, which are the result of carboxylic acids undergoing reaction with reagents such as chloroformates or EEDQ. The two carbonyls of these substrates are not equivalent, and amines typically add to the desired carbonyl due to the lower electrophilicity of the undesired carbonyl (i.e., carbonate). That is the reason why ethyl chloroformate affords good selectivity for amide bond formation at the desired carbonyl despite lacking steric bulk. Reagents to prepare these mixed carboxylic or carbonic anhydrides are typically added to a solution of the carboxylic acid in the presence of a base, such as NMM or Nmethylpiperidine. These mixed anhydrides commonly are carried into coupling with the amine without isolation. Acetic anhydride (Ac2O) is commonly used on large scale as an electrophile for amine acetylation;13ah,21 however, it is rarely used as a reagent for acid activation in amide couplings13a as the resulting mixed anhydride demonstrates poor regioselectivity in reactions with amines. There are several large-scale examples in which pivaloyl chloride (PivCl), or trimethylacetyl chloride, has been used to activate acids for amide coupling on large scale.13aj,17d,22 Pivaloyl chloride affords mixed anhydrides with imposing steric bulk to drive the desired regioselectivity for amine addition. Furthermore, PivCl seems to be the coupling reagent of choice for the acylation of chiral amine auxiliaries (oxazolidinones22a,c,g−i or pseudoephedrine13aj) on an industrial scale. The advantages of PivCl for scaleup include its relatively low cost, wide availability, and nontoxic pivalic acid as a byproduct after aqueous workup. As an acid chloride, however, this reagent is an irritant, can cause chemical burns on skin contact, and must be handled on large scale with proper ventilation. 143



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2.2.2. Sulfonate-Based Mixed Anhydrides. Methanesulfonyl chloride (MsCl) and p-toluenesulfonyl chloride (TsCl) are the two reagents in this category that have been employed on large scale for amide bond formation (Figure 3). Sulfonate-based

of T3P on industrial scale. This reagent has low toxicity (LD50 > 2000 mg/kg),33b long shelf life stability, easy handling (commercially available as 50% solutions in organic solvents, such as EtOAc, DMF, or MeCN), and its water-soluble byproducts are extracted readily into aqueous waste streams. Furthermore, T3P appears to be a reagent of choice for suppressing epimerization in the coupling of chiral acids bearing a sensitive α-stereocenter.26,35a,c,f−h Drawbacks of this reagent include its moderate cost and the environmental impact of generating phosphonate waste streams. Ethylmethylphosphinic anhydride (EMPA) is far less common than T3P as a coupling reagent for large-scale amidations.36 EMPA demonstrates enhanced stability toward hydrolysis which allows for peptide synthesis in aqueous media; however, its relatively high toxicity (LD50 = 7 mg/kg) and the need for its low level purging from drug substances have contributed to the limited use of this reagent on industrial scale.33b The mechanism of acid activation with EMPA is similar to the one with T3P. 2.2.4. CDI. CDI, or 1,1′-carbonyldiimidazole, is a very attractive reagent for amide coupling on a large scale.13aa,19ac,ae,35b,37 It is inexpensive, widely available on kilogram scale as a crystalline solid, relatively safe, and its byproduct imidazole is easily purged with aqueous workup. The reaction of a carboxylic acid with CDI generates a transient mixed anhydride that rearranges to a carbonyl imidazolide (Scheme 5). This carbonyl imidazolide is relatively easy to handle and may be isolated if necessary. Rearrangement of the initial mixed anhydride to the carbonyl imidazolide generates an equivalent of CO2 which can accelerate the rate of subsequent amide coupling.38 An additional advantage is that CDI-promoted couplings are often performed without additional base, as the liberated imidazole can serve this function. One drawback of this reagent is its sensitivity toward atmospheric moisture.39 2.3. Coupling via Activated Ester. 2.3.1. Carbodiimides. The use of DCC, or N,N′-dicyclohexylcarbodiimide, for the formation of peptide and other amide bonds was first reported by Sheehan and Hess in 1955.40 Since that time, carbodiimides have been an extremely important class of compounds for the efficient preparation of amide bonds.41 Many carbodiimides have been investigated as coupling reagents, but only a few are routinely used on large scale based on availability, cost, isolation, and environmental considerations (Figure 5). This group is comprised of DCC, DIC (N,N′-diisopropylcarbodiimide), and EDC (1-ethyl-3-(3′-dimethylaminopropyl)-carbodiimide hydrochloride, also known as EDAC, EDCI, or WSC (water-soluble carbodiimide)). These compounds are skin

Figure 3. Reagents for amide coupling via sulfonate-based anhydrides.

mixed anhydrides derived from either reagent display excellent selectivity in which amines add preferentially to the activated carbonyl instead of the sulfonate ester. MsCl has not been used commonly for large-scale amide couplings.22f,29 MsCl is highly toxic, corrosive, moisturesensitive, and a lachrymator,30 and these properties contribute to the challenge of handling this reagent in industrial processes. However, MsCl is relatively inexpensive and has been shown to suppress epimerization for the coupling of chiral acids.29b TsCl is used even less frequently than MsCl for large-scale amide formation.31 TsCl is widely available and inexpensive, but also toxic and hygroscopic. 2.2.3. Phosphorus-Based Mixed Anhydrides. The first example of a mixed carboxylic−phosphoric anhydride was reported in 1972 using diphenylphosphoryl azide.32 However, no examples using this reagent for acid activation have been found in the large scale literature, most likely due to the cost and high energy and toxicity of the azido group. On the other hand, more scale-friendly reagents such as n-propanephosphonic acid anhydride (T3P) and ethylmethylphosphinic anhydride (EMPA) (Figure 4) have been applied by process chemistry groups for the synthesis of drug candidates.

Figure 4. Reagents for amide coupling via phosphorus-based anhydrides.

n-Propanephosphonic acid anhydride, more commonly referred to as T3P (or PPA), was developed in 198033 as a reagent for peptide couplings (Scheme 4).34 The past decade has realized an uptake in this reagent for large-scale amide couplings.26,31a,35 Several factors contribute to the attractiveness Scheme 4. Mechanism of Acid Activation with T3P

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Scheme 5. Mechanism for CDI-Mediated Amide Coupling

Figure 5. Carbodiimides routinely used on scale.

The O-acylisourea can also rearrange by intramolecular acyl transfer to give the N-acylurea, which is an irreversible pathway that does not lead to desired amide. The use of auxiliary nucleophiles is a common practice to reduce N-acylurea formation and α-stereocenter epimerization by increasing the overall rate of amide coupling. Although many additives have been reported, 1-hydroxybenzotriazole (HOBt)42 is by far the most commonly used for carbodiimide-mediated reactions in either stoichiometric or catalytic fashion (Figure 6). HOBt is

sensitizers to varying degrees and should be handled with caution. A primary consideration when selecting a carbodiimide is the preferred workup since the method for removal of the urea byproduct can vary widely. For example, dicyclohexylurea from DCC has very limited solubility in most organic solvents and, therefore, is typically removed by filtration. Diisopropylurea from DIC has reasonable solubility in CH2Cl2 and is normally removed by aqueous extraction. Finally, the byproduct urea from EDC is water-soluble and can be removed by aqueous workup. The mechanism of carbodiimide-mediated coupling is complex and begins with proton transfer from the carboxylic acid to the weakly basic nitrogen on the carbodiimide to give an ion pair (Scheme 6). Addition of the resulting carboxylate

Figure 6. Epimerization suppressants HOBt and HOAt.

Scheme 6. Pathways for Carbodiimide-Mediated Amidation

shock sensitive and subject to travel regulations,49 whereas analog 1-hydroxy-7-azabenzotriazole (HOAt) is more stable but considerably more expensive. These additives function by intercepting the O-acylisourea before intramolecular acyl transfer to the N-acylurea. The resulting activated ester is active enough to couple with the amine, which circumvents epimerization in many cases. The application of DCC for amide bond formation is showcased in the numerous reports from pharmaceutical companies.22d,24a,35a,43 Despite being a strong sensitizer, its low cost is one of the main drivers for its widespread use. Compared to DCC, DIC has seen more limited use in process chemistry groups,24d,44 despite being a liquid which makes it easier to handle on plant scale. EDC45 is by far the most widely used carbodiimide for the synthesis of drug candidates.13r,17k,l,v,19m,n,21l,24b,28,35b,46 The fact that the urea byproduct is water-soluble and can be removed during the aqueous workup offers a clear advantage over other carbodiimides such as DCC and DIC. However, the high cost of this reagent is an issue that may disfavor its use over other alternatives on scale, especially in late development. 2.3.2. Phosphonium Salts. BOP ((benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate, Castro’s reagent, Figure 7)47 was the first reagent of the HOBt-based

anion forms the O-acylisourea, a very reactive acylating agent that rapidly undergoes aminolysis with an amine to give the desired amide. Alternatively, excess carboxylic acid can react with the O-acylisourea to form the symmetrical anhydride, which is also a good acylating agent. Acylation of an amine with the symmetrical anhydride also produces an equivalent of the starting acid. 145



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Figure 7. BOP and PyBOP coupling reagents.

onium salts to be introduced for amide bond formation to avoid epimerization and other side reactions that can take place with carbodiimide reagents. Despite promoting fast couplings and containing the epimerization suppressant HOBt in its structure, BOP has seen limited use in process chemistry due to the generation of one equivalent of hexamethylphosphoramide (HMPA), a known carcinogen. As an alternative, PyBOP ((benzotriazol-1-yloxy)tris(pyrrolidine)phosphonium hexafluorophosphate, Figure 7) was developed,48 which produces the more benign tris(pyrrolidin-1-yl)phosphine oxide, but this reagent is relatively expensive, and no examples have been found describing its use on large scale. Another important consideration is the presence of the high-energy benzotriazole moiety, which requires the implementation of thorough safety studies to determine the viability of the protocol.49 The mechanism of acid activation with BOP is shown in Scheme 7. In the presence of a base such as Et3N or the preferred i-Pr2 NEt, the acid carboxylate displaces the benzotriazolyloxy anion from the phosphonium center to produce an acyloxyphosphonium intermediate. This species then reacts with the benzotriazolyloxy anion to give an activated benzotriazole ester and water-soluble HMPA as the byproduct. The final step involves the reaction of the benzotriazole ester with the amine nucleophile to afford the desired amide product and HOBt as byproduct. The application of BOP in process chemistry has been very limited due to the drawbacks mentioned above, and only one example is included in this review.50 2.3.3. Guanidinium and Uronium Salts. Benzotriazolebased HBTU, or N-[(1H-benzotriazol-1-yl) (dimethylamino)methylene]-N-methylmethanaminium hexafluorophosphate Noxide,51 was introduced shortly after BOP for amide coupling (Figure 8). Since then, a large number of guanidinium and uronium salts have been reported,1k and the structural elucidation of these reagents as guanidinium versus uronium salts has been investigated.51c These reagents afford fast amide bond formations and can be very useful for the coupling of sterically hindered amino acids in peptide synthesis. Despite these advantages, only HBTU, HATU (N-[(dimethylamino)1H-1,2,3-triazolo[4,5-b]pyridin-1-ylmethylene]-N-methylme-

Figure 8. Guanidinium and uronium salts HBTU, HATU, TBTU, TPTU, and TOTU.

thanaminium hexafluorophosphate N-oxide), TBTU (N-[(1Hbenzotriazol-1-yl) (dimethylamino)methylene]-N-methylmethanaminium tetrafluoroborate N-oxide), TPTU (2-(2-oxo1(2H)-pyridyl-1,1,3,3-tetramethyluronium tetrafluoroborate), and TOTU (O-[(cyano(ethoxycarbonyl)methyleneamino]N,N,N′,N′-tetramethyluronium tetrafluoroborate) have found their way into large scale applications for the synthesis of pharmaceuticals (Figure 8). In comparative studies between HATU and HBTU, it has been shown that the counteranion has no appreciable effect on the outcome of the reaction.51a,52 Some reasons for the limited application of these reagents in process chemistry include their high molecular weight (which translates to high cost per mole),14 the formation of cytotoxic N,N,N′,N′-tetramethylurea as a byproduct,53 and the presence of high energy functional groups such as the triazolyl moiety in HBTU, HATU, and TBTU and the N−O bonds in TPTU and TOTU. Nevertheless, the use of these reagents may be justified in situations where sensitive functionality is present on the coupling partners, and as a consequence, mild reaction conditions are required. A typical example is when the

Scheme 7. Mechanism of Acid Activation with BOP

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Scheme 8. Acid Activation and Amide Bond Formation with HBTU

carboxylic acid contains an epimerizable α-stereocenter. In these cases, the addition of 1 equiv of either HOBt or HOAt (Figure 6) may further suppress epimerization. The mechanism of amide bond formation using guanidinium and uronium salts is similar to the one described above for BOP and is exemplified in Scheme 8 for HBTU. Acid activation requires the formation of the corresponding carboxylate anion with bases such as Et3N or i-Pr2NEt as the first step. The carboxylate anion then reacts with HBTU to form an activated HOBt ester and tetramethylurea as byproduct, which is the driving force for acid activation. The reaction of the amine with the HOBt ester yields the desired amide product. Interestingly, although HBTU is widely used for solid-phase peptide synthesis, only one application of this reagent has been found among process chemistry groups for the manufacture of drug candidates.54 HATU55 is a structurally very close analog to HBTU, but it provides faster couplings with less epimerization. This reagent has seen widespread use as coupling reagent for amide bond formation due to the mild reaction conditions and the usually high yields of amide product that it provides. It is also particularly efficient for sterically hindered couplings.55,56 For these reasons, several process groups in pharmaceutical companies have reported HATU applications for the synthesis of drug candidates.57 Several examples on the application of TBTU52 by process chemistry groups have been reported.17d,37ae,58 The reagent provides very fast couplings, and it can be particularly attractive when the carboxylic acid contains an epimerizable α-stereocenter. HOBt can be used in combination with TBTU to reduce epimerization further. TPTU46b and TOTU35a,36 have seen very limited application on large scale, most likely due to cost reasons. 2.3.4. Triazine-Based Coupling Reagents. This family of reagents encompasses several compounds that have been employed on scale (Figure 9). Due to conflicting reports on their type of acid activation (as acid chloride or activated ester; vide infra), these reagents are grouped together in this section as converting carboxylic acids to activated triazine esters. Cyanuric chloride (1,3,5-trichlorotriazine) is a highly reactive coupling reagent produced on the industrial scale by the hundreds of thousands of metric tons per year via trimerization of cyanogen chloride. As a result, it is one of the most costeffective coupling reagents for amide bond formation. Due to the presence of three chlorine atoms on the molecule acting as leaving groups, this reagent can be employed in substoichio-

Figure 9. Structure of triazine-derived cyanuric chloride, CDMT, and DMTMM.

metric quantities. The mechanism for acid activation with cyanuric chloride has generally been described as proceeding via acid chloride formation (Scheme 9).1b The acid must be in the carboxylate form to displace the chloride and form the activated ester intermediate, which then reacts with the chloride to afford the desired acid chloride and byproduct 1,3-dichloro5-hydroxytriazine. Reaction of the latter with another two molecules of carboxylic acid can afford cyanuric acid as byproduct. However, there has also been a report from the process chemistry group at Rohm and Haas Company in which an acid chloride from cyanuric chloride was not detected; instead, acid activation was proposed to take place via an activated ester (Scheme 10).59 Amine bases such as Et3N and NMM are commonly used with cyanuric chloride, but inexpensive inorganic bases such as NaOH can also be employed and the reaction can be conducted in the presence of water. The resulting cyanuric acid byproduct can be easily removed during workup via filtration or basic washes. In spite of these clear advantages, cyanuric chloride has received little attention from process chemists in the pharmaceutical industry.17i,59 CDMT, or 2-chloro-4,6-dimethoxy-1,3,5-triazine,60 can be easily synthesized from the reaction of cyanuric chloride and 2 equiv of methanol in the presence of Na2CO3 as base. It is a stable, crystalline solid that is commercially available in bulk. This reagent has been shown to be effective at reducing epimerization and, also, to work with sterically hindered primary and secondary alkyl and aryl amines.61 CDMT usually 147



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Scheme 9. Mechanism for Acid Chloride Generation with Cyanuric Acid1b

Scheme 10. Mechanism for Activated Ester Generation with Cyanuric Acid59

requires the use of a tertiary amine base, such as NMM, for acid activation, and the coupling can be carried out in solvents such as THF, DMF, and EtOAc. In comparison to cyanuric chloride and DMTMM (vide infra), CDMT has seen more widespread use across process groups in the pharmaceutical industry13d,61,62 despite the relatively high cost per mole. A typical experimental procedure is the addition of the tertiary amine base to a mixture of acid, amine, and CDMT.61 The mechanism for acid activation with CDMT is also a matter of debate, and as for cyanuric chloride, activation via acid chloride1a,d or via activated ester59 have been proposed. Regardless of the mode of activation, 1-hydroxy-3,5-dimethoxytriazine is generated as byproduct. DMTMM, or 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride,63 an air and water-stable solid that can be easily prepared from CDMT by treatment with NMM, has been scarcely used in process chemistry.62c An advantage of this reagent is that it can be employed for amide bond formation in alcoholic or aqueous solvents without the generation of the corresponding esters or hydrolysis product.64 DMTMM activation provides an activated ester with NMM·HCl as byproduct (Scheme 11).1d The reagent can be added to a mixture of the acid and amine coupling partners. The addition of acid carboxylate to DMTMM liberates NMM which acts as a base to promote the amide coupling. 1-Hydroxy-3,5-dimethoxytriazine is a water-soluble byproduct that can be removed by aqueous workup. However, as was mentioned previously for CDMT, the relatively high cost per mole of DMTMM is a deterring factor for its application on large scale. 2.4. Coupling via Boron Species. The use of boronderived reagents as catalysts for amide bond formation has increased considerably in recent years.1g,65 The original reports required the use of stoichiometric amounts of boron reagents,66,67 but more recently, Yamamoto and co-workers have described the first examples with substoichiometric amounts.68,69

Scheme 11. Acid Activation Mechanism with DMTMM via Activated Ester

Many boron-based reagents have been reported for amide bond formation outside of process chemistry: boric acid,70 trimethoxyborane,66a boron trifluoride-etherate,66c catecholborane,66d borane−trimethylamine,66e phenylboronic acid,71 obromo and o-iodoarylboronic acid,72,73 3,4,5-trifluorophenylboronic acid,68a,74 N,N-diisopropylbenzylamine-2-boronic acid,74b,75 trifluoroethoxyborane,76 borate esters,77 3,5-bis(perfluorodecyl)phenylboronic acid,68b N-alkyl-4-boronopyridinium halides,78 4,5,6,7-tetrachlorobenzo[d][1,3,2]dioxaborol-2ol,79 and 3-nitrophenylboronic acid.68a However, despite the many choices available, boric acid clearly stands out as a very desirable reagent since it is inexpensive and displays excellent atom economy (Figure 10). In addition, after reaction completion, the water-soluble reagent can be extracted into an aqueous workup. On the other hand, drawbacks of boric acid are reproductive toxicity at high doses80 and that the European Chemical Agency may include it on the list of high concern substances which would restrict its use in Europe.81 148



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Scheme 13. Amide Bond Formation during the Synthesis of API 4

Figure 10. Boron-derived reagents used on scale.

Boron reagents for amide bond formation82 have seen limited use in process chemistry, and only examples with boric acid83 and 3-nitrophenylboronic acid84 have been found (Figure 10). The proposed mechanism for amide formation catalyzed by boric acid is shown in Scheme 12,70 and a similar mechanism Scheme 12. Mechanism for Carboxylic Acid Activation and Amide Bond Formation with Boric Acid

and amine 3, which the medicinal chemistry group had carried out using the EDC/HOBt combination. However, the high cost and limited commercial availability of EDC as well as the hazards involved in the handling of HOBt49 led to the search for a coupling method more amenable for large-scale operations. In addition, it was necessary to obtain full consumption of amine 3; otherwise, the isolation of 4 proved to be difficult. T3P/NMM gave partial conversion and some degradation byproducts, whereas the preparation of activated esters (N-hydroxysuccinimide (NHS), N-hydroxybenzotriazole (HOBt)) via treatment with (COCl)2, acid chlorides, or chloroformates provided low yields of the activated esters and polymeric byproducts derived from acid 1. However, treatment of 1 with either SOCl2 or POCl3 led to the formation of acid chloride 2, which could be isolated as a crystalline solid. In order to get full conversion to the desired API 4, a screen was carried out that looked at both organic (pyridine, DMAP, NMM, imidazole) and inorganic (Na2CO3, NaHCO3) bases, which revealed imidazole as the best choice. On laboratory scale, acid 1 in THF was treated with 1.25 equiv of SOCl2 and, after stirring at 0 °C for 1 h, the mixture was concentrated followed by coevaporation with n-heptane to azeotropically distill SOCl2. The residue was redissolved in DMF and this solution was added to a solution of amine 3 and imidazole in EtOAc at 0 °C. After stirring overnight at rt, an aqueous workup, and crystallization from n-heptane/EtOAc, amide 4 was isolated in 92% yield (two crops). Walker and co-workers at Parke-Davis have described the synthesis of compounds 8 and 9, two candidates evaluated as antiretroviral agents for the treatment of AIDS (Scheme 14).13e The synthesis of 8 commenced with the preparation of diacid chloride 6, which was obtained after treating diacid 5 with SOCl2 (2.8 equiv) and catalytic DMF in toluene. After 16 h at 70−75 °C, residual SOCl2 was removed by distillation, and 6 was crystallized from toluene in 83% yield on multikilogram scale. With diacid chloride 6 on hand, the researchers investigated the amide bond formation leading to 8. Several esters of L-isoleucine (methyl, benzyl, allyl) were tested in amide coupling, but the subsequent ester cleavage step was not satisfactory in all three cases. As a result, the direct coupling with L-isoleucine itself was attempted. Thus, a solvent screen

can be envisioned for arylboronic acids.85 Reaction of a carboxylic acid and boric acid leads to the formation of an activated mixed anhydride intermediate after the loss of a molecule of water (water must be removed azeotropically to displace the equilibrium toward the acylated boronic acid intermediate). This intermediate then reacts with the amine to afford the amide product and regenerate boric acid, which restarts the catalytic cycle. The mechanism for amide bond formation with arylboronic acids has also been investigated in silico.86

3. OTHER METHODS FOR AMIDE BOND FORMATION Not all of the following large-scale examples fall into the category of acid activation for amide bond formation; however, they are referenced in this review since some approaches have been employed frequently. 3.1. Synthesis of Amides from Esters. Esters have been converted to amides by direct treatment with the corresponding amine. Reports employing methyl esters,21p,43i,46u,z,87 ethyl esters,19e,ah,ap,88 tert-butyl esters,89 isobutyl esters,90 benzyl esters, 19aa lactones, 91 thioesters, 92 pentafluorophenyl esters,24i,93 and N-hydroxysuccinimido esters18,43d,94 have been published. 3.2. Synthesis of Amides via Transamidation. Although not commonly practiced, one example of intramolecular transamidation has been reported on large scale for amide synthesis.22h 3.3. Synthesis of Amides Catalyzed by Brö nsted Acids. Finally, Brönsted acids can catalyze amide bond formation, as has been reported for AcOH,95 H2SO4,96 and TFA.97 4. CASE STUDIES 4.1. Coupling via Acid Chloride. 4.1.1. Thionyl Chloride. Stoner and co-workers at Abbott Laboratories have reported the preparation of HIV protease inhibitor 4 (Scheme 13).13g The last step of the synthesis involved the coupling of acid 1 149



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Scheme 14. Synthesis of Drug Candidates 8 and 9 via Diamide Bond Formation

Scheme 15. Amide Bond Formation En Route to L-Alanyl-Lglutamine (16)

was chosen for further development due to the enhanced chemical and optical stability of this substrate compared to the bromo analogue. In addition, 12 could be prepared in higher optical purity than D-2-bromopropionyl-L-glutamine from Dalanine, L-lactate, or via enzymatic resolution of D , Lchloropropionic acid or its ester. In the plant, acid 12 was treated with a slight excess of SOCl2 at 85 °C for 1 h followed by dilution with toluene to afford acid chloride 13 as a toluene solution. This mixture was then added to a cold (0−5 °C) solution of L-glutamine (14) in an aqueous NaOH/toluene mixture and further stirred at 10 °C and pH = 10 for 1 h. After reaction completion and aqueous workup, the aqueous layer containing the Na salt of 15 was acidified to pH 2 with HCl which crystallized the carboxylic acid in 82% yield and 99.7% de. Zanka and co-workers at Fujisawa Pharmaceutical Co. Ltd. have reported the synthesis of compound 23, a nonxanthine adenosine A1 receptor antagonist for the regulation of renal function (Scheme 16).13i The penultimate step of the synthesis involved the coupling of acid 17 and amine 19. Acid 17 was activated through treatment with equimolar amounts of SOCl2 and DMF (in situ generation of Vilsmeier reagent) to afford acid chloride 18. Prior to the amide-forming step, the hydroxy group in amine 19 was protected as the TMS ether through reaction with N,N′-bis(trimethylsilyl)urea (20) in CH2Cl2. During optimization of the amide coupling, the use of NMM as base led to low yields, whereas other bases such as Et3N or i-Pr2NEt generated dark impurities. However, the addition of catalytic DMAP increased the coupling rate when using Et3N as base and provided amide 22 in excellent yield. In the plant, a mixture of acid 17 and SOCl2 in CH2Cl2 was dosed with DMF (equimolar amount per SOCl2) to generate acid chloride 18. Separately, a cooled solution of amine 21 in CH2Cl2 was dosed with DMAP and Et3N followed by the solution of acid chloride 18. After 1 h, the reaction underwent an aqueous workup, and TMS-protected intermediate 22 was treated with methanolic K2CO3 to cleave the TMS ether and afford crude 23. Recrystallization from EtOH/H2O afforded over 17 kg of API in 99.8% chemical purity and 99% ee. 4.1.2. Oxalyl Chloride. The process group at Albany Molecular Research has reported the coupling of acid chloride 25 and trimethylhydrazine (26) as part of the synthesis of 28, a drug candidate with growth hormone-releasing properties

(dioxane, MTBE, di-n-butyl ether, THF) revealed that THF provided the best yield and purity. Further optimization showed that inorganic bases such as NaHCO3 led to improved yields and purities (NaHCO3 performed better than Na2CO3 and K2CO3 in this respect). In the plant, a mixture of acid chloride, L-isoleucine, and NaHCO3 in THF was heated at 60− 65 °C for 2 h. After reaction completion, the mixture was quenched into diluted aqueous HCl (to neutralize the base) and MTBE. Phase separation was greatly facilitated when the aqueous layer was kept acidic. Following workup, diamide 8 was crystallized from n-hexane/THF and recrystallized from the same solvent mixture to generate 53.6 kg of material in 75% yield and excellent purity (98.7%, area % by HPLC). The experimental conditions including the use of L-isoleucine rather than an ester derivative contributed to maintaining the chiral integrity of 7. The only two relevant impurities detected in 8 were half acid 10 and compound 11 (Figure 11), which is produced due to the presence of trace amounts of L-valine in commercial L-isoleucine.

Figure 11. Impurities detected during the synthesis of diamide 8.

Sugaya and co-workers at Sakai Research Laboratories in Japan have reported the synthesis of L-alanyl-L-glutamine (16), a compound employed as a component of parenteral nutrition (Scheme 15).13j The preparation of intermediate 15 involved the amide bond formation between acid chloride 13 and amine 14. Originally, the α-bromo analogue of 12 was employed and treated with SOCl2 to generate the corresponding acid chloride. On scale, however, this acid chloride tended to decompose under Schotten−Baumann conditions, and the resulting amide showed epimerization and lower purity than in laboratory experiments. As a result, D-2-chloropropionyl-L-glutamine (12) 150



Review

Vilsmeier reagent generation) and Et3N as base in CH2Cl2 to generate 25 which, without isolation, underwent reaction with a solution of trimethylhydrazine in dioxane at −20 °C to provide 27 in 82−90% yield after aqueous workup and purification via silica gel plug. Key to the success of this approach was the order of addition of reagents. Thus, when Et3N was added prior to the (COCl)2 and DMF, only unreacted 24 was recovered, presumably due to the different reactivity of the ammonium salt of acid 24. In addition, the Boc-protecting group was found to be compatible with these reaction conditions, and this protocol was carried out to produce 3.2 kg of amide 27. Magnus and co-workers at Eli Lilly have described the synthesis of glucokinase activator 32 for the treatment of type 2 diabetes (Scheme 18).17q The last step of the synthesis involved

Scheme 16. Amide Coupling of an Amino Alcohol via Transient Hydroxy Protection

Scheme 18. Amide Bond Formation as the Last Step of the Synthesis of API 32

(Scheme 17).17e Several methods were attempted for the coupling of acid 24 and trimethylhydrazine. Initial efforts with Scheme 17. Coupling of Acid Chloride 25 and Trimethylhydrazine En Route to Drug Candidate 28

the amide coupling of carboxylic acid 29 and 2-aminopyrazine (31). During a previous synthesis implemented by the pharmaceutical company Prosidion,98 the aminopyrazine was added to acid chloride 30 at −45 °C which led to the formation of peracylated products. The formation of these impurities was prevented by reversing the order of addition. Thus, acid chloride 30, generated with (COCl)2 and catalytic DMF in THF below 30 °C, was added to a solution of aminopyrazine and pyridine while still maintaining the internal temperature below 30 °C. After 1 h, the byproduct pyridine·HCl was removed via filtration. Following an aqueous workup to remove excess pyridine and 4−5% of acid 29 via acid−base extractions, API 32 was crystallized from MeOH in 74% yield (88−94% in situ yield). Despite the presence of an epimerizable chiral center on the acid moiety, this protocol avoided racemization, and 32 was obtained in >99% ee. Another report from the process group at Eli Lilly describes the synthesis of compound 38, a PPARα agonist for the potential treatment of dyslipidemia, coronary heart disease, and diabetes (Scheme 19).17g The synthesis of intermediate amide 36 was initiated by treating carboxylic acid 33 with 1.15 equiv of (COCl)2 and catalytic DMF in EtOAc below 30 °C which, after distillation of excess (COCl)2, afforded acid chloride 34 as a solution in EtOAc. The removal of excess (COCl)2 was required to keep the level of impurity 39 below 1% (Figure 12). Acid chloride 34 was then added to a solution of amine salt 35 and pyridine in EtOAc. Although the coupling product 36 could be isolated via crystallization, the researchers decided to telescope it into the subsequent cyclization involving camphorsulfonic acid at reflux to afford 37 and side-product

PyBrop (bromotripyrrolidinophosphonium hexafluorophosphate), T3P, CDI, or EDC led to poor conversion or decomposition. The researchers mentioned that these attempts afforded the activated acid species, but the subsequent coupling failed likely due to the steric hindrance provided by the quaternary center at the α position. Despite the presence of the acid-sensitive Boc protecting group in 24, the researchers attempted this coupling through the preparation of acid chloride 25. Thus, acid 24 was treated with 1.6 equiv of (COCl)2 followed by the addition of catalytic DMF (in situ 151



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Scheme 19. Amide Bond Formation during the Synthesis of PPARα Agonist 38

Scheme 20. Amide Bond Formation with POCl3 en Route to 45

Figure 12. Side-products from the coupling of 34 and 35 in the presence of excess (COCl)2.

40 in 15:1 ratio. Treatment of the resulting solution with Amberlyst-15 resin allowed for the selective removal of 40 via filtration, and 37 was crystallized from MTBE with an overall yield of 55% from acid 33. 4.1.3. Phosphorus Oxychloride. An example of amide coupling via POCl3 has been reported by scientists at Otsuka Pharmaceutical during the preparation of drug candidate 45, an inhibitor of superoxide anion generation for the treatment of ischemia and inflammation (Scheme 20).18 Prior to the pyrazinone cyclization, the required amide bond was generated from carboxylic acid 41 via POCl3 activation in the presence of catalytic DMF to produce acid chloride 42, which was telescoped as a CH2Cl2 solution. The amine coupling partner 43 was freebased with aqueous K2CO3 and telescoped as a CH2Cl2 solution. In the amidation step, the acid chloride was added to 43 while holding the temperature between 4−19 °C, and after an aqueous workup, amide 44 was crystallized from cold IPA/H2O in 88% yield on multikilogram scale. 4.1.4. Commercial Vilsmeier Reagent. The process group at Novartis in Switzerland has described the preparation of drug candidate 50 for the treatment of inflammation (Scheme 21).12e The medicinal chemistry group employed EDC/DMAP for the coupling of acid 46 and L-tert-leucine-N-methylamide (48), but epimerization (>5%) was observed. As a result, alternative coupling reagents were investigated. The formation

of a mixed anhydride with isobutyl chloroformate (IBCF) was clean but led to considerable amounts of recovered 46 due to competitive addition of amine to the undesired carbonyl of the mixed anhydride. Other reagents such as CDI and CDMT gave poor results as well. However, commercial Vilsmeier reagent afforded a very clean coupling without detectable epimerization and was therefore chosen for further development. On the 152



Review

4.2.2. Pivaloyl Chloride (PivCl). Li and co-workers at Neurocrine Biosciences synthesized amide 57 via the PivClmediated coupling of acid 55 and pseudoephedrine (56) en route to valnoctamide (59), a mild sedative (Scheme 23).13aj

Scheme 21. Amidation via Vilsmeier Reagent Acid Activation en Route to API 50

Scheme 23. PivCl-Mediated Coupling of Acid 55 and Pseudoephedrine

laboratory scale, acid 46 was treated with 1.5 equiv of Vilsmeier reagent in THF to afford acid chloride 47. After the resulting suspension was stirred at 0 °C for 1 h, the addition of NMM followed by a solution of amine 48, and catalytic DMF in THF provided almost 50 g of amide 49 (98% yield). 4.2. Coupling via Carboxylic or Carbonic Acid Mixed Anhydride. 4.2.1. Acetic Anhydride. As noted above, acetic anhydride is not a common reagent for acid activation en route to amide coupling. However, one such example was demonstrated by Hoekstra and co-workers at Parke−Davis for the synthesis of pregabalin (Lyrica, 54).13a As demonstrated in Scheme 22, 3-isobutylglutaric acid (51) and Ac2O were

The mixed anhydride was first prepared by dosing a cooled solution of acid 55 and Et3N in CH2Cl2 with PivCl. After treating this mixed anhydride with a second charge of Et3N, pseudoephedrine was added portionwise while maintaining a temperature below 5 °C. The amine was added as a solid to minimize reaction volume, and 99% achiral, 0.5% ent112) and purging of pyridine, excess aminonicotinate 111, and T3P byproducts to the mother liquor. A related study from Pfizer demonstrated the combination of T3P and pyridine as a general method for suppressing epimerization in the amide coupling of other carboxylic acids bearing a sensitive αstereocenter.35g Patterson and co-workers at GlaxoSmithKline developed a one-pot amidation/dehydration to complete their large-scale synthesis of denagliptin (87), a treatment for type II diabetes (Scheme 35).26 The coupling of acid 114 and pyrrolidine 115 with T3P and Hünig’s base provided amide 116 without any epimerization. The subsequent dehydration of primary carboxamide to nitrile proved more difficult, as several reagents led to degradation or incomplete conversion. Initially, the dehydration was accomplished on 150 kg scale by treating a

Scheme 34. T3P and Pyridine To Suppress Epimerization in Amidation

Scheme 35. Synthesis of Denagliptin via One-Pot Amidation and Dehydration Using T3P

condensation of α-imidazolyl acid 110 and aminonicotinate 111 led to racemization, including T3P in initial screens, but the epimerization from T3P was reduced when switching the base from Et3N to bulkier (TMP) or weaker alternatives (pyridines, morpholines). Several evolutions of this coupling were demonstrated in the pilot plant, and ultimately the pairing 157



Review

solution of 116 in EtOAc (after aqueous workup and azeotropic drying distillation) with methanesulfonic anhydride and pyridine to afford the nitrile in 90% yield. However, it was discovered that performing the T3P coupling of acid 114 and pyrrolidine 115 at higher temperature led to 87 as a dehydration byproduct, and this observation led to a secondgeneration process for a one-pot amidation/dehydration with both steps facilitated by T3P. In this streamlined approach, the amide bond was formed with an initial dose of T3P (1.5 equiv) in EtOAc at 50 °C. After reaction completion, a second dose of T3P (1.5 equiv) was added, and the mixture was heated at reflux (∼78 °C) to effect the dehydration. After aqueous workup, 123 kg of denagliptin was crystallized from IPA for an excellent 97% yield over two steps. Gudmundsson, Xie, and co-workers at GSK used T3P to convert picolinate salt 117 to picolinamide 118, a treatment for human papillomavirus infections (Scheme 36).35d This is an

Scheme 37. Forming a Piperidine Amide via Ethylmethylphosphinic Anhydride

Scheme 36. T3P-Mediated Conversion of Picolinate Salt to Picolinamide

Scheme 38. Amide Coupling via Imidazolide 123 for Synthesis of Trimethobenzamide (125)

interesting case in which amine 117 was crystallized previously with one equivalent of 2-picolinic acid, the same acid to be incorporated into the active pharmaceutical ingredient. A solution of the amine salt and Hünig’s base in CH2Cl2 at 0 °C was dosed with T3P to cleanly generate picolinamide 118, and an additional 0.1 equiv of 2-picolinic acid were added to ensure reaction completion. After aqueous workup to remove the T3P byproducts, solvent exchange and crystallization from EtOH provided 9.7 kg of picolinamide 118. The authors mentioned that this T3P procedure was more practical than alternative acylations via the acid chloride or O-benzotriazole activation. 4.4.2. Ethylmethylphosphinic Anhydride (EMPA). Colleagues at Hoechst AG and Behring Werke used EMPA to install a piperidine amide in their kilogram-scale synthesis of thrombin inhibitor 121 (Scheme 37).36 A solution of acid 119 and piperidine in EtOAc was dosed with a solution of EMPA in EtOAc to form amide 120. Aqueous workup and solvent evaporation provided 5.7 kg of 120 as a yellow oil. The authors also described similar EMPA-mediated couplings of two other acids with piperidine on multigram scale. 4.5. Coupling via CDI. Neelakandan and co-workers at Emcure Pharmaceutical Limited and Annamalai University incorporated CDI into an improved amidation process for the synthesis of trimethobenzamide (125; Tigan), an antiemetic agent for nausea (Scheme 38).37ac Various reagents for the coupling of trimethoxybenzoic acid 122 and benzylamine 124, including SOCl2, tert-butyl chloroformate, DCC/DMAP, EDC/ HOBt, and boric acid, led to demethylation impurities 126 and 127 that were difficult to purge from the desired amide without yield loss. Alternatively, CDI provided a relatively clean amidation from the demethylation impurities; however, the formation of urea 128 became an issue if this coupling reagent were used in too large an excess. Stoichiometry studies

identified 1.25 equiv of CDI as optimal for efficient coupling while maintaining impurities 126−128 below regulatory limits after crystallizing the product trimethobenzamide from acetone and aqueous HCl. Weisenburger and co-workers at Pfizer reported the process development of a CDI-mediated peptide coupling for the preparation of αvβ3 integrin antagonist 132 (Scheme 39).37q The original route for preclinical supplies of 132 involved the reaction of amine 130 with the N-hydroxysuccinimide (NHS) ester of N-Boc glycine (129), but the high cost of this NHS ester prompted the team to explore alternative reagents for the coupling of 129. Ultimately, CDI was chosen for its relatively 158



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Scheme 39. Inverse Addition of Carbonyl Imidazolide to Amine 130

Scheme 40. CDI-Mediated Amide Coupling and Ritter Reaction

low cost and the ease of removing imidazole salt byproducts by aqueous extraction. On laboratory scale, the carbonyl imidazolide of 129 was prepared by charging solvent to dissolve equal amounts of amino acid and CDI (both solids); however, this approach led to the rapid release of CO2 which was unsuitable for pilot plant production. Alternatively, on large scale, the imidazolide formation was controlled by adding a solution of 129 to a slurry of CDI, which led to minor foaming but no increase in pressure. The subsequent addition of amine 130 to the activated glycine led to a mixture of amide 131 and byproduct from the O-acetylation of 132 at the phenolic alcohol. Aging this mixture for several hours improved the ratio of 131 to overacetylation byproduct, presumably from the addition of unreacted amine 130 to the byproduct’s phenolic ester to provide two molecules of 131. The rate of Oacetylation increased exponentially as the concentration of amine decreased, and the byproduct was held to 97% de). Further purification by recrystallization from EtOH/water afforded amide product with >99% de in 74% yield. The process group at Lilly has described the preparation of drug candidate 222, a multitargeted antifolate for the treatment of cancer (Scheme 62).62a Acid 219 was activated using CDMT

Scheme 63. DMTMM as Coupling Reagent en Route to Drug Candidate 226

Scheme 62. Synthesis of API 222 via CDMT-Promoted Amide Formation

224 was the epimerization of the chiral center in 223. Initial experiments with DMTMM, CDMT, and IBCF led to considerable racemization (8−30%), most likely due to the increased acidity of the benzylic proton in 223 upon activated ester formation. At lower temperature, DMTMM provided the best results compared to CDMT and IBCF, and by using free base 224 rather than its HCl salt, an increased reaction rate was observed which also contributed to minimizing racemization to only 1.5% epimer. On laboratory scale, 224·HCl was treated with Cs2CO3 in aqueous THF (19:1 v/v THF:H2O) at ambient temperature to generate the free base of 224. To this mixture was then added a solution of acid 223 in toluene. Solid DMTMM was added in several portions, and the reaction was cooled at −5 °C for 16 h. Following an aqueous workup, amide 225 was isolated as a toluene solution that was telescoped into the next step (ester and amide reduction with BH3·THF). Amide 225 was obtained in 96:4 er with only 2% epimerization from acid 223 (98:2 er). 4.10. Coupling via Boron Reagent. 4.10.1. Boric Acid. Boric acid has been employed by the process chemistry group at GlaxoSmithKline for the preparation of efaproxiral (230), a commercial drug for the treatment of cancer (Scheme 64).83a Substrates such as carboxylic acid 228, with a phenol functionality on the molecule, usually need protection of the hydroxy group prior to amide bond formation. However, the

in DMF at 25 °C for 1 h followed by the addition of L-glutamic acid diethyl ester·HCl (220). Upon reaction completion, an aqueous workup isolated the free base of 221 as a CH2Cl2 solution, which was converted to over 11 kg of the p-TsOH salt. An interesting observation is that the amino group on the pyrimidone did not require protection prior to the amide bond step. 4.9.3. DMTMM. An example of the application of DMTMM in process chemistry is found in the preparation of cannabinoid1 antagonist 226, a drug candidate for the treatment of obesity and diabetes, by Villhauer, Shieh, and co-workers at Novartis 167



Review

of acid 233 and chiral amine 232 to reflux in the presence of catalytic boric acid (5.5 mol%) under Dean−Stark conditions. After 16−18 h, an aqueous workup was performed, and crude amide 234 was isolated in 76% yield and used in the next step (amide reduction) without further purification. 4.10.2. 3-Nitrophenylboronic Acid. Brookes and co-workers at Celltech−Chiroscience in the U.K. have reported the largescale preparation of the two enantiomers of verapamil·HCl (235; Figure 14), a commercial drug for the treatment of

Scheme 64. Synthesis of Amide 229 en Route to Efaproxiral

Figure 14. Structure of (±)-verapamil·HCl.

use of B(OH)3 (0.1 equiv) allowed for the coupling of unprotected 228 and aniline 227 in toluene at reflux under Dean−Stark conditions. The resulting amide crystallized upon cooling and was isolated in 86−95% yield on multigram scale. The addition of boric acid dramatically reduced the reaction time and temperature in comparison to the protocol reported by the medicinal chemistry group, which coupled 227 and 228 in xylene at reflux for 3 days with no catalyst. Mathad and co-workers at Megafine Pharma and the chemistry department at B. H. Commerce and A. M. Science College in India have published the syntheses of several impurities detected during the industrial preparation of cinacalcet·HCl (231; Sensipar, Mimpara; Figure 13), a calcimimetic agent for the treatment of hyperparathyroidism.83c

cardiovascular conditions.84 Verapamil is currently administered as the racemate, but due to the different biological effects of the two enantiomers, the development of routes to each individual enantiomer would be advantageous. For the preparation of (S)-verapamil·HCl ((S)-236, Scheme 66), chiral acid 238 was obtained via classical resolution of its racemate with (S)-α-methylbenzylamine (both enantiomers of this amine are readily available and, thus, either enantiomer of the acid is accessible) to give diastereomeric salt 237. After salt break, acid 238 (>95% ee) was telescoped as a xylene solution into reaction with amine 239 in the presence of catalytic 3nitrophenylboronic acid68a (0.5 mol%) at reflux. Following an aqueous workup and concentration, the amide solution was seeded with 240 and cooled to afford 480 g of desired amide in 85% yield. This amide bond formation step could also be carried out with catalytic boric acid, but this reagent was less efficient and higher loadings were required (10−20 mol%).

5. CONCLUSIONS The importance of amide bond formation in process chemistry for the synthesis of drug candidates cannot be overstated. Process chemists have a wide array of methods at their disposal to generate amides, but the limitations imposed by large-scale operations have focused the selection to a narrower field of reagents. Based on the number of examples included in this review, the top choices for acid activation by reagent are EDC, SOCl2, CDI, and (COCl)2, followed by a second group that includes PivCl, IBCF, T3P, and DCC. Most of the reagents presented in this review are used in stoichiometric amounts, and some of them, such as the guanidinium and uronium salts, are very atom-inefficient. As a consequence, the American Chemical Society Green Chemistry Pharmaceutical Roundtable has selected the development of more environmentally friendly and efficient methods for amide bond formation as one of their top priorities.106 The development of catalytic processes for amide bond formation has seen a resurgence in recent years. Boron-derived reagents, such as the ones described in sections 2.4 and 4.10 of this review, have already been implemented on large scale in several instances. Besides boron, catalytic methods that employ zinc,107 titanium,108 zirconium,109 aluminum,110 indium,111 silica,112 and niobium113 are very promising discoveries that, with further development, may have the chance to enter the process chemistry arena and displace some of the more traditional stoichiometric approaches. Also, enzymes have

Figure 13. Structure of cinacalcet·HCl.

One of the impurities described in the article is compound 235 (Scheme 65), which contains a cyclohexyl ring in place of the phenyl ring in cinacalcet. (The origin of this impurity was tracked to 1-(3-bromopropyl)-3-(trifluoromethyl)benzene, one of the reagents employed in a previous N-alkylation step.) The preparation of amide 234 was carried out by heating a solution Scheme 65. Boric Acid-Promoted Synthesis of CinacalcetRelated Impurity

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Scheme 66. Amide Bond Formation Catalyzed by 3-Nitrophenylboronic Acid en Route to (S)-Verapamil·HCl

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received considerable attention recently as a green approach to synthesizing primary, secondary, and tertiary amides,1p with lipases encompassing most examples. This family of catalysts is highly selective, and the amidation can be carried out in a number of green solvents such as water and alcohols. However, current technologies show very limited substrate scope and often require long reaction times (days). Other efforts have investigated safer alternatives to benzotriazole-based coupling reagents. As a result, oxymabased reagents such as COMU (1-[(1-cyano-2-ethoxy-2oxoethylideneaminooxy)-dimethylaminomorpholinomethylene)]methanaminium hexafluorophosphate)114 have emerged as safer replacements with comparable reactivities. Finally, alternatives to the traditional coupling between a carboxylic acid and an amine for amide synthesis have also been pursued. A remarkable example is the ruthenium-catalyzed coupling of an amine and an alcohol which generates one equivalent of dihydrogen as the only byproduct.115 High yields were obtained with as little as 0.1 mol% Ru catalyst, and no additives or stoichiometric oxidant were needed. This transformation has also been accomplished with catalytic ZnI2 and stoichiometric tert-butyl hydroperoxide.107b Another example is the preparation of amides from functionalized aldehydes (formylcyclopropanes, α,β-unsaturated aldehydes, α-haloaldehydes, epoxyaldehydes).116 Regardless of reagent choice, amide bond formation will undoubtedly continue to be one of the most important transformations in process chemistry for the synthesis of pharmaceuticals. Societal and economic pressures are already having a clear effect on driving safer, greener, and cheaper reagents and methods. We are confident that, if proven scalable, many of these new technologies will be routinely incorporated into large-scale operations for the synthesis of API.

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ABBREVIATIONS API: active pharmaceutical ingredient(s) aq: aqueous Bn: benzyl Boc: tert-butoxycarbonyl BOP: (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate Cbz: carbonylbenzyloxy CDI: 1,1′-carbonyldiimidazole CDMT: 2-chloro-4,6-dimethoxy-1,3,5-triazine CSA: camphorsulfonic acid DCC: N,N′-dicyclohexylcarbodiimide DCU: N,N′-dicyclohexylurea de: diastereomeric excess DIC: N,N′-diisopropylcarbodiimide DMAc: N,N-dimethylacetamide DMAP: N,N-dimethylaminopyridine DME: 1,2-dimethoxyethane DMF: N,N-dimethylformamide DMTMM: 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride ECF: ethyl chloroformate EDAC: 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide EDC or EDCI: 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide EEDQ: 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline EMPA: ethylmethylphosphinic anhydride ee: enantiomeric excess equiv: equivalent(s) er: enantiomeric ratio GC: gas chromatography HATU: N-[(dimethylamino)-1H-1,2,3-triazolo[4,5-b]pyridin-1-ylmethylene]-N-methylmethanaminium hexafluorophosphate N-oxide HBTU: N-[(1H-benzotriazol-1-yl) (dimethylamino)methylene]-N-methylmethanaminium hexafluorophosphate N-oxide HCV: hepatitis C virus HOAt: 1-hydroxy-7-azabenzotriazole HOBt: N-hydroxybenzotriazole HONB: N-hydroxy-5-norbornene-endo-2,3-dicarboxylic acid imide HOOBt: 3,4-dihydro-3-hydroxy-4-oxo-(1,2,3)-benzotriazine HPLC: high performance liquid chromatography

AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected]. *E-mail: Javier.Magano@Pfizer.com. *E-mail: Gerald.A.Weisenburger@Pfizer.com. Notes

The authors declare no competing financial interest. 169



Review

(7) Wigman, L.; Remarchuk, T.; Gomez, S. R.; Kumar, A.; Dong, M. W.; Medley, C. D.; Chetwyn, N. P. Am. Pharm. Rev. 2014, 17, 20. (8) (a) Magano, J.; Dunetz, J. R. Chem. Rev. 2011, 111, 2177. (b) Magano, J.; Dunetz, J. R. Org. Process Res. Dev. 2012, 16, 1156. (9) Fischer, E.; Otto, E. Ber. Dtsch. Chem. Ges. 1903, 36, 2106. (10) Fieser, L. F.; Fieser, M. Reagents for Organic Synthesis; Wiley: New York, 1969; Vol. 1, p 286. (11) Li, J. J. In Name Reactions: a Collection of Detailed Mechanisms and Synthetic Applications, 3rd ed.; Springer: New York, 2006; p 605. (12) Commercial Vilsmeier reagent: (a) Zanka, A. Org. Process Res. Dev. 1998, 2, 418. (b) Singh, J.; Kim, O. K.; Kissick, T. P.; Natalie, K. J.; Zhang, B.; Crispino, G. A.; Springer, D. M.; Wichtowski, J. A.; Zhang, Y.; Goodrich, J.; Ueda, Y.; Luh, B. Y.; Burke, B. D.; Brown, M.; Dutka, A. P.; Zheng, B.; Hsieh, D.-M.; Humora, M. J.; North, J. T.; Pullockaran, A. J.; Livshits, J.; Swaminathan, S.; Gao, Z.; Schierling, P.; Ermann, P.; Perrone, R. K.; Lai, M. C.; Gougoutas, J. Z.; DiMarco, J. D.; Bronson, J. J.; Heikes, J. E.; Grosso, J. A.; Kronenthal, D. R.; Denzel, T. W.; Mueller, R. H. Org. Process Res. Dev. 2000, 4, 488. (c) Totleben, M. J.; Prasad, J. S.; Simpson, J. H.; Chan, S. H.; Vanyo, D. J.; Kuehner, D. E.; Deshpande, R.; Kodersha, G. A. J. Org. Chem. 2001, 66, 1057. (d) Gibson, F. S.; Singh, A. K.; Soumeillant, M. C.; Manchand, P. S.; Humora, M.; Kronenthal, D. R. Org. Process Res. Dev. 2002, 6, 814. (e) Koch, G.; Kottirsch, G.; Wietfeld, B.; Küsters, E. Org. Process Res. Dev. 2002, 6, 652. (13) Thionyl chloride: (a) Hoekstra, M. S.; Sobieray, D. M.; Schwindt, M. A.; Mulhern, T. A.; Grote, T. M.; Huckabee, B. K.; Hendrickson, V. S.; Franklin, L. C.; Granger, E. J.; Karrick, G. L. Org. Process Res. Dev. 1997, 1, 26. (b) Wu, G.; Wong, Y.; Steinman, M.; Tormos, W.; Schumacher, D. P.; Love, G. M.; Shutts, B. Org. Process Res. Dev. 1997, 1, 359. (c) Zhang, L.-h.; Chung, J. C.; Costello, T. D.; Valvis, I.; Ma, P.; Kauffman, S.; Ward, R. J. Org. Chem. 1997, 62, 2466. (d) Johnson, E. P.; Cantrell, W. R.; Jenson, T. M.; Miller, S. A.; Parker, D. J.; Reel, N. M.; Sylvester, L. G.; Szendroi, R. J.; Vargas, K. J.; Xu, J.; Carlson, J. A. Org. Process Res. Dev. 1998, 2, 238. (e) Fiore, P. J.; Puls, T. P.; Walker, J. C. Org. Process Res. Dev. 1998, 2, 151. (f) Cook, D. C.; Jones, R. H.; Kabir, H.; Lythgoe, D. J.; McFarlane, I. M.; Pemberton, C.; Thatcher, A. A.; Thompson, D. M.; Walton, J. B. Org. Process Res. Dev. 1998, 2, 157. (g) Stoner, E. J.; Stengel, P. J.; Cooper, A. J. Org. Process Res. Dev. 1999, 3, 145. (h) Dale, D. J.; Dunn, P. J.; Golightly, C.; Hughes, M. L.; Levett, P. C.; Pearce, A. K.; Searle, P. M.; Ward, G.; Wood, A. S. Org. Process Res. Dev. 2000, 4, 17. (i) Zanka, A.; Uematsu, R.; Morinaga, Y.; Yasuda, H.; Yamazaki, H. Org. Process Res. Dev. 1999, 3, 389. (j) Sano, T.; Sugaya, T.; Inoue, K.; Mizutaki, S.-i.; Ono, Y.; Kasai, M. Org. Process Res. Dev. 2000, 4, 147. (k) Pflum, D. A.; Wilkinson, H. S.; Tanoury, G. J.; Kessler, D. W.; Kraus, H. B.; Senanayake, C. H.; Wald, S. A. Org. Process Res. Dev. 2001, 5, 110. (l) Ikemoto, T.; Ito, T.; Hashimoto, H.; Kawarasaki, T.; Nishiguchi, A.; Mitsudera, H.; Wakimasu, M.; Tomimatsu, K. Org. Process Res. Dev. 2000, 4, 520. (m) Fang, Q. K.; Grover, P.; Han, Z.; McConville, F. X.; Rossi, R. F.; Olsson, D. J.; Kessler, D. W.; Wald, S. A.; Senanayake, C. H. Tetrahedron: Asymmetry 2001, 12, 2169. (n) Phillips, G.; Fevig, T. L.; Lau, P. H.; Klemm, G. H.; Mao, M. K.; Ma, C.; Gloeckner, J. A.; Clark, A. S. Org. Process Res. Dev. 2002, 6, 357. (o) Tan, L.; Chen, C.y.; Chen, W.; Frey, L.; King, A. O.; Tillyer, R. D.; Xu, F.; Zhao, D.; Grabowski, E. J. J.; Reider, P. J.; O’Shea, P.; Dagneau, P.; Wang, X. Tetrahedron 2002, 58, 7403. (p) Allegretti, M.; Anacardio, R.; Cesta, M. C.; Curti, R.; Mantovanini, M.; Nano, G.; Topai, A.; Zampella, G. Org. Process Res. Dev. 2003, 7, 209. (q) Ager, D. J.; Babler, S.; Erickson, R. A.; Froen, D. E.; Kittleson, J.; Pantaleone, D. P.; Prakash, I.; Zhi, B. Org. Process Res. Dev. 2004, 8, 72. (r) Farr, R. N.; Alabaster, R. J.; Chung, J. Y. L.; Craig, B.; Edwards, J. S.; Gibson, A. W.; Ho, G.-J.; Humphrey, G. R.; Johnson, S. A.; Grabowski, E. J. J. Tetrahedron: Asymmetry 2003, 14, 3503. (s) Cai, S.; Dimitroff, M.; McKennon, T.; Reider, M.; Robarge, L.; Ryckman, D.; Shang, X.; Therrien, J. Org. Process Res. Dev. 2004, 8, 353. (t) Moher, E. D.; Tripp, A. E.; Creemer, L. C.; Vicenzi, J. T. Org. Process Res. Dev. 2004, 8, 593. (u) Ikemoto, T.; Ito, T.; Nishiguchi, A.; Miura, S.; Tomimatsu, K. Org. Process Res. Dev. 2005, 9, 168. (v) Kotian, P. L.; Lin, T.-H.; El-Kattan, Y.; Chand, P. Org. Process Res. Dev. 2005, 9, 193. (w) Iida, T.; Satoh, H.; Maeda,

IBCF: isobutyl chloroformate IPA: isopropanol, or 2-propanol LD50: median lethal dose LDA: lithium diisopropylamide LiHMDS: lithium hexamethyldisilazide MsCl: methanesulfonyl chloride MTBE: tert-butyl methyl ether NaHMDS: sodium hexamethyldisilazide NHS: N-hydroxysuccinimide NMI: N-methylimidazole NMM: N-methylmorpholine NMP: N-methyl-2-pyrrolidone PPA: n-propanephosphonic acid anhydride Piv: pivaloyl py: pyridine PyBOP: (ben zotriazol-1-y lo xy )tris(py rrolidine)phosphonium hexafluorophosphate PyBrop: bromotripyrrolidinophosphonium hexafluorophosphate rt: room temperature T3P: n-propanephosphonic acid anhydride TBTU: N-[(1H-benzotriazol-1-yl) (dimethylamino)methylene]-N-methylmethanaminium tetrafluoroborate Noxide TFA: trifluoroacetic acid THF: tetrahydrofuran TMP: 2,2,6,6-tetramethylpiperidine TMS: trimethylsilyl TOTU: O-[(cyano(ethoxycarbonyl)methyleneamino]N,N,N′,N′-tetramethyluronium tetrafluoroborate TPTU: 2-(2-oxo-1(2H)-pyridyl-1,1,3,3-tetramethyluronium tetrafluoroborate TsCl: p-toluenesulfonyl chloride WSC: water-soluble carbodiimide

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REFERENCES

(1) Amidation reviews since 2004: (a) Han, S.-Y.; Kim, Y.-A. Tetrahedron 2004, 60, 2447. (b) Montalbetti, C. A. G. N.; Falque, V. Tetrahedron 2005, 61, 10827. (c) Bode, J. W. Curr. Opin. Drug Discovery Dev. 2006, 9, 765. (d) Valeur, E.; Bradley, M. Chem. Soc. Rev. 2009, 38, 606. (e) Ishihara, K. Tetrahedron 2009, 65, 1085. (f) Joullié, M. M.; Lassen, K. M. ARKIVOC 2010, 8, 189. (g) Charville, H.; Jackson, D.; Hodges, G.; Whiting, A. Chem. Commun. 2010, 46, 1813. (h) Scheidt, K. Nature 2010, 465, 1020. (i) Pattabiraman, V. R.; Bode, J. W. Nature 2011, 480, 471. (j) Allen, C. L.; Williams, J. M. J. Chem. Soc. Rev. 2011, 40, 3405. (k) El-Faham, A.; Albericio, F. Chem. Rev. 2011, 111, 6557. (l) Roy, S.; Roy, S.; Gribble, G. W. Tetrahedron 2012, 68, 9867. (m) Al-Warhi, T. I.; Al-Hazimi, H. M. A.; El-Faham, A. J. Saudi Chem. Soc. 2012, 16, 97. (n) Bode, J. W. Top. Organomet. Chem. 2013, 44, 13. (o) Lanigan, R. M.; Sheppard, T. D. Eur. J. Org. Chem. 2013, 7453. (p) Lundberg, H.; Tinnis, F.; Selander, N.; Adolfsson, H. Chem. Soc. Rev. 2014, 43, 2714. (q) Taylor, J. E.; Bull, S. D. In Comprehensive Organic Synthesis, 2nd ed.; Knochel, P., Molander, G. A., Eds.; Elsevier: New York, 2014; pp 427−478. (2) Carey, J. S.; Laffan, D.; Thomson, C.; Williams, M. T. Org. Biomol. Chem. 2006, 4, 2337. (3) Roughley, S. D.; Jordan, A. M. J. Med. Chem. 2011, 54, 3451. (4) Charville, H.; Jackson, D. A.; Hodges, G.; Whiting, A.; Wilson, M. R. Eur. J. Org. Chem. 2011, 5981. (5) (a) Jursic, B. S.; Zdravkovski, Z. Synth. Commun. 1993, 23, 2761. (b) Goossen, L. J.; Ohlmann, D. M.; Lange, P. P. Synthesis 2009, 160. (6) (a) Caddick, S. Tetrahedron 1995, 51, 10403. (b) Varma, R. S. Green Chem. 1999, 1, 43. (c) Perreux, L.; Loupy, A.; Volatron, F. Tetrahedron 2002, 58, 2155. 170



Review

Thavonekham, B. Can. J. Chem. 2000, 78, 739. (e) García-Rubio, S.; Wilson, C. D.; Renner, D. A.; Rosser, J. O.; Patra, D.; Reid, J. G.; Pines, S. H. Org. Process Res. Dev. 2004, 8, 360. (f) Li, H.; Xia, Z.; Chen, S.; Koya, K.; Ono, M.; Sun, L. Org. Process Res. Dev. 2007, 11, 246. (g) Braden, T. M.; Coffey, D. S.; Doecke, C. W.; LeTourneau, M. E.; Martinelli, M. J.; Meyer, C. L.; Miller, R. D.; Pawlak, J. M.; Pedersen, S. W.; Schmid, C. R.; Shaw, B. W.; Staszak, M. A.; Vicenzi, J. T. Org. Process Res. Dev. 2007, 11, 431. (h) Beylin, V.; Boyles, D. C.; Curran, T. T.; Macikenas, D.; Parlett, R. V.; Vrieze, D. Org. Process Res. Dev. 2007, 11, 441. (i) Chen, C.-y.; Frey, L. F.; Shultz, S.; Wallace, D. J.; Marcantonio, K.; Payack, J. F.; Vazquez, E.; Springfield, S. A.; Zhou, G.; Liu, P.; Kieczykowski, G. R.; Chen, A. M.; Phenix, B. D.; Singh, U.; Strine, J.; Izzo, B.; Krska, S. W. Org. Process Res. Dev. 2007, 11, 616. (j) Miyazaki, H.; Ohmizu, H.; Ogiku, T. Org. Process Res. Dev. 2009, 13, 760. (k) O’Shea, P. D.; Gauvreau, D.; Gosselin, F.; Hughes, G.; Nadeau, C.; Roy, A.; Shultz, C. S. J. Org. Chem. 2009, 74, 4547. (l) Sawai, Y.; Yamane, T.; Ikeuchi, M.; Kawaguchi, S.; Yamada, M.; Yamano, M. Org. Process Res. Dev. 2010, 14, 1110. (m) Huang, X.; O’Brien, E.; Thai, F.; Cooper, G. Org. Process Res. Dev. 2010, 14, 592. (n) Humphrey, G. R.; Pye, P. J.; Zhong, Y.-L.; Angelaud, R.; Askin, D.; Belyk, K. M.; Maligres, P. E.; Mancheno, D. E.; Miller, R. A.; Reamer, R. A.; Weissman, S. A. Org. Process Res. Dev. 2011, 15, 73. (o) Gauvreau, D.; Dolman, S. J.; Hughes, G.; O’Shea, P. D.; Davies, I. W. J. Org. Chem. 2010, 75, 4078. (p) Baxter, C. A.; Cleator, E.; Brands, K. M. J.; Edwards, J. S.; Reamer, R. A.; Sheen, F. J.; Stewart, G. W.; Strotman, N. A.; Wallace, D. J. Org. Process Res. Dev. 2011, 15, 367. (q) Magnus, N. A.; Braden, T. M.; Buser, J. Y.; DeBaillie, A. C.; Heath, P. C.; Ley, C. P.; Remacle, J. R.; Varie, D. L.; Wilson, T. M. Org. Process Res. Dev. 2012, 16, 830. (r) Wang, X.-j.; Zhang, L.; Sun, X.; Lee, H.; Krishnamurthy, D.; O’Meara, J. A.; Landry, S.; Yoakim, C.; Simoneau, B.; Yee, N. K.; Senanayake, C. H. Org. Process Res. Dev. 2012, 16, 561. (s) Patil, G. D.; Kshirsagar, S. W.; Shinde, S. B.; Patil, P. S.; Deshpande, M. S.; Chaudhari, A. T.; Sonawane, S. P.; Maikap, G. C.; Gurjar, M. K. Org. Process Res. Dev. 2012, 16, 1422. (t) Ronn, M.; Zhu, Z.; Hogan, P. C.; Zhang, W.-Y.; Niu, J.; Katz, C. E.; Dunwoody, N.; Gilicky, O.; Deng, Y.; Hunt, D. K.; He, M.; Chen, C.-L.; Sun, C.; Clark, R. B.; Xiao, Z.-Y. Org. Process Res. Dev. 2013, 17, 838. (u) Karlsson, S.; Brånalt, J.; Halvarsson, M. Ö .; Bergman, J. Org. Process Res. Dev. 2014, 18, 969. (v) Eisenbeis, S. A.; Chen, R.; Kang, M.; Barrila, M.; Buzon, R. Org. Process Res. Dev. 2015, 19, 244. (18) Phosphorus oxychloride: Tone, H.; Matoba, K.; Goto, F.; Torisawa, Y.; Nishi, T.; Minamikawa, J.-i. Org. Process Res. Dev. 2000, 4, 312. (19) Commercial acid chlorides: (a) Fang, F. G.; Bankston, D. D.; Huie, E. M.; Johnson, M. R.; Kang, M.-C.; LeHoullier, C. S.; Lewis, G. C.; Lovelace, T. C.; Lowery, M. W.; McDougald, D. L.; Meerholz, C. A.; Partridge, J. J.; Sharp, M. J.; Xie, S. Tetrahedron 1997, 53, 10953. (b) Zanka, A.; Nishiwaki, M.; Morinaga, Y.; Inoue, T. Org. Process Res. Dev. 1998, 2, 230. (c) Konoike, T.; Oda, K.; Uenaka, M.; Takahashi, K. Org. Process Res. Dev. 1999, 3, 347. (d) Ennis, D. S.; McManus, J.; Wood-Kaczmar, W.; Richardson, J.; Smith, G. E.; Carstairs, A. Org. Process Res. Dev. 1999, 3, 248. (e) Fleitz, F. J.; Lyle, T. A.; Zheng, N.; Armstrong, J. D.; Volante, R. P. Synth. Commun. 2000, 30, 3171. (f) Caron, S.; Massett, S. S.; Bogle, D. E.; Castaldi, M. J.; Braish, T. F. Org. Process Res. Dev. 2001, 5, 254. (g) Urban, F. J.; Anderson, B. G.; Orrill, S. L.; Daniels, P. J. Org. Process Res. Dev. 2001, 5, 575. (h) Zhao, M. M.; McNamara, J. M.; Ho, G.-J.; Emerson, K. M.; Song, Z. J.; Tschaen, D. M.; Brands, K. M. J.; Dolling, U.-H.; Grabowski, E. J. J.; Reider, P. J.; Cottrell, I. F.; Ashwood, M. S.; Bishop, B. C. J. Org. Chem. 2002, 67, 6743. (i) Magnus, N. A.; Confalone, P. N.; Storace, L.; Patel, M.; Wood, C. C.; Davis, W. P.; Parsons, R. L. J. Org. Chem. 2003, 68, 754. (j) Reichard, G. A.; Spitler, J.; Mergelsberg, I.; Miller, A.; Wong, G.; Raghavan, R.; Jenkins, J.; Gan, T.; McPhail, A. T. Tetrahedron: Asymmetry 2002, 13, 939. (k) Kumar, Y.; Tewari, N.; Nizar, H.; Rai, B. P.; Singh, S. K. Org. Process Res. Dev. 2003, 7, 933. (l) Hasegawa, T.; Kawanaka, Y.; Kasamatsu, E.; Iguchi, Y.; Yonekawa, Y.; Okamoto, M.; Ohta, C.; Hashimoto, S.; Ohuchida, S. Org. Process Res. Dev. 2003, 7, 168. (m) Gauthier, D. R.; Ikemoto, N.; Fleitz, F. J.; Szumigala, R. H.; Petrillo, D.; Liu, J.; Reamer, R. A.; Armstrong, J. D.; Yehl, P. M.; Wu,

K.; Yamamoto, Y.; Asakawa, K.-i.; Sawada, N.; Wada, T.; Kadowaki, C.; Itoh, T.; Mase, T.; Weissman, S. A.; Tschaen, D.; Krska, S.; Volante, R. P. J. Org. Chem. 2005, 70, 9222. (x) Nikitenko, A. A.; Winkley, M. W.; Zeldis, J.; Kremer, K.; Chan, A. W. Y.; Strong, H.; Jennings, M.; Jirkovsky, I.; Blum, D.; Khafizova, G.; Grosu, G. T.; Venkatesan, A. M. Org. Process Res. Dev. 2006, 10, 712. (y) Peters, R.; Althaus, M.; Diolez, C.; Rolland, A.; Manginot, E.; Veyrat, M. J. Org. Chem. 2006, 71, 7583. (z) Oh, L. M.; Wang, H.; Shilcrat, S. C.; Herrmann, R. E.; Patience, D. B.; Spoors, P. G.; Sisko, J. Org. Process Res. Dev. 2007, 11, 1032. (aa) Barkalow, J. H.; Breting, J.; Gaede, B. J.; Haight, A. R.; Henry, R.; Kotecki, B.; Mei, J.; Pearl, K. B.; Tedrow, J. S.; Viswanath, S. K. Org. Process Res. Dev. 2007, 11, 693. (ab) Satyanarayana, K.; Srinivas, K.; Himabindu, V.; Reddy, G. M. Org. Process Res. Dev. 2007, 11, 842. (ac) Moseley, J. D.; Brown, D.; Firkin, C. R.; Jenkin, S. L.; Patel, B.; Snape, E. W. Org. Process Res. Dev. 2008, 12, 1044. (ad) HaycockLewandowski, S. J.; Wilder, A.; Åhman, J. Org. Process Res. Dev. 2008, 12, 1094. (ae) Åhman, J.; Birch, M.; Haycock-Lewandowski, S. J.; Long, J.; Wilder, A. Org. Process Res. Dev. 2008, 12, 1104. (af) Busacca, C. A.; Cerreta, M.; Dong, Y.; Eriksson, M. C.; Farina, V.; Feng, X.; Kim, J.-Y.; Lorenz, J. C.; Sarvestani, M.; Simpson, R.; Varsolona, R.; Vitous, J.; Campbell, S. J.; Davis, M. S.; Jones, P.-J.; Norwood, D.; Qiu, F.; Beaulieu, P. L.; Duceppe, J.-S.; Haché, B.; Brong, J.; Chiu, F.-T.; Curtis, T.; Kelley, J.; Lo, Y. S.; Powner, T. H. Org. Process Res. Dev. 2008, 12, 603. (ag) Agbodjan, A. A.; Cooley, B. E.; Copley, R. C. B.; Corfield, J. A.; Flanagan, R. C.; Glover, B. N.; Guidetti, R.; Haigh, D.; Howes, P. D.; Jackson, M. M.; Matsuoka, R. T.; Medhurst, K. J.; Millar, A.; Sharp, M. J.; Slater, M. J.; Toczko, J. F.; Xie, S. J. Org. Chem. 2008, 73, 3094. (ah) Klapars, A.; Campos, K. R.; Waldman, J. H.; Zewge, D.; Dormer, P. G.; Chen, C.-y. J. Org. Chem. 2008, 73, 4986. (ai) Wallace, D. J.; Campos, K. R.; Shultz, C. S.; Klapars, A.; Zewge, D.; Crump, B. R.; Phenix, B. D.; McWilliams, J. C.; Krska, S.; Sun, Y.; Chen, C.-y.; Spindler, F. Org. Process Res. Dev. 2009, 13, 84. (aj) Li, B.-F.; Hughes, R. M.; Le, J.; McGee, K.; Gallagher, D. J.; Gross, R. S.; Provencal, D.; Reddy, J. P.; Wang, P.; Zegelman, L.; Zhao, Y.; Zook, S. E. Org. Process Res. Dev. 2009, 13, 463. (ak) Webel, M.; Palmer, A. M.; Scheufler, C.; Haag, D.; Müller, B. Org. Process Res. Dev. 2010, 14, 142. (al) Bret, G.; Harling, S. J.; Herbal, K.; Langlade, N.; Loft, M.; Negus, A.; Sanganee, M.; Shanahan, S.; Strachan, J. B.; Turner, P. G.; Whiting, M. P. Org. Process Res. Dev. 2011, 15, 112. (am) Chandramouli, S. V.; Ayers, T. A.; Wu, X.-D.; Tran, L. T.; Peers, J. H.; Disanto, R.; Roberts, F.; Kumar, N.; Jiang, Y.; Choy, N.; Pemberton, C.; Powers, M. R.; Gardetto, A. J.; D’Netto, G. A.; Chen, X.; Gamboa, J.; Ngo, D.; Copeland, W.; Rudisill, D. E.; Bridge, A. W.; Vanasse, B. J.; Lythgoe, D. J. Org. Process Res. Dev. 2012, 16, 484. (an) Sera, M.; Yamashita, M.; Ono, Y.; Tabata, T.; Muto, E.; Ouchi, T.; Tawada, H. Org. Process Res. Dev. 2014, 18, 446. (ao) Rousseau, J.-F.; Chekroun, I.; Ferey, V.; Labrosse, J. R. Org. Process Res. Dev. 2015, 19, 506. (ap) Oda, S.; Manaka, K.; Kakiya, K.; Hozumi, Y.; Fukui, Y.; Omura, S.; Kurashita, M.; Nishiwaki, M.; Takeuchi, Y.; Kitamura, H. Org. Process Res. Dev. 2015, 19, 531. (14) Anderson, N. G. In Practical Process Research & Development: A Guide for Organic Chemists, 2nd ed.; Academic Press: New York, 2012; p 109. (15) Levin, D. Org. Process Res. Dev. 1997, 1, 182. (16) Stare, M.; Laniewski, K.; Westermark, A.; Sjögren, M.; Tian, W. Org. Process Res. Dev. 2009, 13, 857. (17) Oxalyl chloride: (a) Maligres, P. E.; Weissman, S. A.; Upadhyay, V.; Cianciosi, S. J.; Reamer, R. A.; Purick, R. M.; Sager, J.; Rossen, K.; Eng, K. K.; Askin, D.; Volante, R. P.; Reider, P. J. Tetrahedron 1996, 52, 3327. (b) Horgan, S. W.; Burkhouse, D. W.; Cregge, R. J.; Freund, D. W.; LeTourneau, M.; Margolin, A.; Webster, M. E.; Henton, D. R.; Barton, K. P.; Clouse, R. C.; DesJardin, M. A.; Donaldson, R. E.; Fetner, N. J.; Goralski, C. T.; Heinrich, G. P.; Hoops, J. F.; Keaten, R. T.; McConnell, J. R.; Nitz, M. A.; Stolz-Dunn, S. K. Org. Process Res. Dev. 1999, 3, 241. (c) Shi, Y.-J.; Wells, K. M.; Pye, P. J.; Choi, W.-B.; Churchill, H. R. O.; Lynch, J. E.; Maliakal, A.; Sager, J. W.; Rossen, K.; Volante, R. P.; Reider, P. J. Tetrahedron 1999, 55, 909. (d) Simoneau, B.; Lavallée, P.; Bailey, M.; Duceppe, J.-S.; Grand-Maître, C.; Grenier, L.; Ogilvie, W. W.; Poupart, M.-A.; 171



Review

N.; Volante, R. P. Tetrahedron: Asymmetry 2003, 14, 3557. (n) Ashwood, M. S.; Alabaster, R. J.; Cottrell, I. F.; Cowden, C. J.; Davies, A. J.; Dolling, U. H.; Emerson, K. M.; Gibb, A. D.; Hands, D.; Wallace, D. J.; Wilson, R. D. Org. Process Res. Dev. 2004, 8, 192. (o) Bio, M. M.; Xu, F.; Waters, M.; Williams, J. M.; Savary, K. A.; Cowden, C. J.; Yang, C.; Buck, E.; Song, Z. J.; Tschaen, D. M.; Volante, R. P.; Reamer, R. A.; Grabowski, E. J. J. J. Org. Chem. 2004, 69, 6257. (p) Mani, N. S.; Jablonowski, J. A.; Jones, T. K. J. Org. Chem. 2004, 69, 8115. (q) Ripin, D. H. B.; Bourassa, D. E.; Brandt, T.; Castaldi, M. J.; Frost, H. N.; Hawkins, J.; Johnson, P. J.; Massett, S. S.; Neumann, K.; Phillips, J.; Raggon, J. W.; Rose, P. R.; Rutherford, J. L.; Sitter, B.; Stewart, A. M.; Vetelino, M. G.; Wei, L. Org. Process Res. Dev. 2005, 9, 440. (r) Peters, R.; Waldmeier, P.; Joncour, A. Org. Process Res. Dev. 2005, 9, 508. (s) Bentley, D.; Godfrey, A. A.; Warren, K. E. H. Org. Process Res. Dev. 2006, 10, 553. (t) Henegar, K. E.; Ball, C. T.; Horvath, C. M.; Maisto, K. D.; Mancini, S. E. Org. Process Res. Dev. 2007, 11, 346. (u) Henegar, K. E.; Cebula, M. Org. Process Res. Dev. 2007, 11, 354. (v) Belecki, K.; Berliner, M.; Bibart, R. T.; Meltz, C.; Ng, K.; Phillips, J.; Ripin, D. H. B.; Vetelino, M. Org. Process Res. Dev. 2007, 11, 754. (w) Beutler, U.; Boehm, M.; Fuenfschilling, P. C.; Heinz, T.; Mutz, J.-P.; Onken, U.; Mueller, M.; Zaugg, W. Org. Process Res. Dev. 2007, 11, 892. (x) Guillaume, M.; Cuypers, J.; Dingenen, J. Org. Process Res. Dev. 2007, 11, 1079. (y) Reuman, M.; Hu, Z.; Kuo, G.-H.; Li, X.; Russell, R. K.; Shen, L.; Youells, S.; Zhang, Y. Org. Process Res. Dev. 2007, 11, 1010. (z) Shu, L.; Wang, P. Org. Process Res. Dev. 2008, 12, 298. (aa) Bowles, D. M.; Bolton, G. L.; Boyles, D. C.; Curran, T. T.; Hutchings, R. H.; Larsen, S. D.; Miller, J. M.; Park, W. K. C.; Ritsema, K. G.; Schineman, D. C.; Tamm, M. Org. Process Res. Dev. 2008, 12, 1183. (ab) Limanto, J.; Dorner, B. T.; Hartner, F. W.; Tan, L. Org. Process Res. Dev. 2008, 12, 1269. (ac) Magnus, N. A.; Astleford, B. A.; Brennan, J.; Stout, J. R.; Tharp-Taylor, R. W. Org. Process Res. Dev. 2009, 13, 280. (ad) Choy, A.; Colbry, N.; Huber, C.; Pamment, M.; Duine, J. V. Org. Process Res. Dev. 2008, 12, 884. (ae) Achmatowicz, M.; Thiel, O. R.; Wheeler, P.; Bernard, C.; Huang, J.; Larsen, R. D.; Faul, M. M. J. Org. Chem. 2009, 74, 795. (af) Hansen, M. M.; Borders, S. S. K.; Clayton, M. T.; Heath, P. C.; Kolis, S. P.; Larsen, S. D.; Linder, R. J.; Reutzel-Edens, S. M.; Smith, J. C.; Tameze, S. L.; Ward, J. A.; Weigel, L. O. Org. Process Res. Dev. 2009, 13, 198. (ag) Yu, K.; Sun, N.; Fang, S.; Mo, W.; Hu, B.; Shen, Z.; Hu, X. Org. Process Res. Dev. 2009, 13, 815. (ah) McDermott, T. S.; Bhagavatula, L.; Borchardt, T. B.; Engstrom, K. M.; Gandarilla, J.; Kotecki, B. J.; Kruger, A. W.; Rozema, M. J.; Sheikh, A. Y.; Wagaw, S. H.; Wittenberger, S. J. Org. Process Res. Dev. 2009, 13, 1145. (ai) N, S. K.; Reddy, S. B.; Sinha, B. K.; Mukkanti, K.; Dandala, R. Org. Process Res. Dev. 2009, 13, 1185. (aj) Rassias, G.; Stevenson, N. G.; Curtis, N. R.; Northall, J. M.; Gray, M.; Prodger, J. C.; Walker, A. J. Org. Process Res. Dev. 2010, 14, 92. (ak) Miao, L.; Xu, L.; Narducy, K. W.; Trudell, M. L. Org. Process Res. Dev. 2009, 13, 820. (al) Gosselin, F.; Lau, S.; Nadeau, C.; Trinh, T.; O’Shea, P. D.; Davies, I. W. J. Org. Chem. 2009, 74, 7790. (am) Chavez, F.; Kennedy, N.; Rawalpally, T.; Williamson, R. T.; Cleary, T. Org. Process Res. Dev. 2010, 14, 579. (an) Faigl, F.; Thurner, A.; Molnár, B.; Simig, G.; Volk, B. Org. Process Res. Dev. 2010, 14, 617. (ao) Jin, Q.; Welch, M.; Fisher, L. Org. Process Res. Dev. 2010, 14, 470. (ap) Pippel, D. J.; Mills, J. E.; Pandit, C. R.; Young, L. K.; Zhong, H. M.; Villani, F. J.; Mani, N. S. Org. Process Res. Dev. 2011, 15, 638. (aq) Chen, J.; Przyuski, K.; Roemmele, R.; Bakale, R. P. Org. Process Res. Dev. 2011, 15, 1063. (ar) Aalla, S.; Gilla, G.; Bojja, Y.; Anumula, R. R.; Vummenthala, P. R.; Padi, P. R. Org. Process Res. Dev. 2012, 16, 682. (as) Ball, M.; Boyd, A.; Churchill, G.; Cuthbert, M.; Drew, M.; Fielding, M.; Ford, G.; Frodsham, L.; Golden, M.; Leslie, K.; Lyons, S.; McKeever-Abbas, B.; Stark, A.; Tomlin, P.; Gottschling, S.; Hajar, A.; Jiang, J.-l.; Lo, J.; Suchozak, B. Org. Process Res. Dev. 2012, 16, 741. (at) Aalla, S.; Gilla, G.; Anumula, R. R.; Kurella, S.; Padi, P. R.; Vummenthala, P. R. Org. Process Res. Dev. 2012, 16, 748. (au) DeBaillie, A. C.; Jones, C. D.; Laurila, M. E.; Magnus, N. A.; Staszak, M. A. Org. Process Res. Dev. 2013, 17, 231. (av) Henegar, K. E.; Lira, R.; Kim, H.; Gonzalez-Hernandez, J. Org. Process Res. Dev. 2013, 17, 985. (aw) Chen, Y.; Crockett, R. D.; Wang, X.; Larsen, R. D.; Cui, S.; Faul, M. M. Synlett 2013, 24, 301. (ax) Sammons, M.; Jennings, S. M.;

Herr, M.; Hulford, C. A.; Wei, L.; Hallissey, J. F.; Kiser, E. J.; Wright, S. W.; Piotrowski, D. W. Org. Process Res. Dev. 2013, 17, 934. (ay) Ishimoto, K.; Fukuda, N.; Nagata, T.; Sawai, Y.; Ikemoto, T. Org. Process Res. Dev. 2014, 18, 122. (az) Hong, J.-B.; Davidson, J. P.; Jin, Q.; Lee, G. R.; Matchett, M.; O’Brien, E.; Welch, M.; Bingenheimer, B.; Sarma, K. Org. Process Res. Dev. 2014, 18, 228. (ba) Yoshida, S.; Marumo, K.; Takeguchi, K.; Takahashi, T.; Mase, T. Org. Process Res. Dev. 2014, 18, 1721. (20) Commercial acid bromides: (a) Kim, B. C.; Kim, K.-Y.; Lee, H. B.; Shin, H. Org. Process Res. Dev. 2008, 12, 626. (b) Straessler, N. A.; Lesley, M. W.; Cannizzo, L. F. Org. Process Res. Dev. 2012, 16, 512. (21) Ac2O for amine acetylation: (a) Rohloff, J. C.; Kent, K. M.; Postich, M. J.; Becker, M. W.; Chapman, H. H.; Kelly, D. E.; Lew, W.; Louie, M. S.; McGee, L. R.; Prisbe, E. J.; Schultze, L. M.; Yu, R. H.; Zhang, L. J. Org. Chem. 1998, 63, 4545. (b) Prabhakar, C.; Kumar, N. V.; Reddy, M. R.; Sarma, M. R.; Reddy, G. O. Org. Process Res. Dev. 1999, 3, 155. (c) Kowalczyk, B. A.; Robinson, J.; Gardner, J. O. Org. Process Res. Dev. 2001, 5, 116. (d) Karpf, M.; Trussardi, R. J. Org. Chem. 2001, 66, 2044. (e) Perrault, W. R.; Pearlman, B. A.; Godrej, D. B.; Jeganathan, A.; Yamagata, K.; Chen, J. J.; Lu, C. V.; Herrinton, P. M.; Gadwood, R. C.; Chan, L.; Lyster, M. A.; Maloney, M. T.; Moeslein, J. A.; Greene, M. L.; Barbachyn, M. R. Org. Process Res. Dev. 2003, 7, 533. (f) Harrington, P. J.; Brown, J. D.; Foderaro, T.; Hughes, R. C. Org. Process Res. Dev. 2004, 8, 86. (g) Angibaud, P. R.; Venet, M. G.; Filliers, W.; Broeckx, R.; Ligny, Y. A.; Muller, P.; Poncelet, V. S.; End, D. W. Eur. J. Org. Chem. 2004, 479. (h) Giles, M. E.; Thomson, C.; Eyley, S. C.; Cole, A. J.; Goodwin, C. J.; Hurved, P. A.; Morlin, A. J. G.; Tornos, J.; Atkinson, S.; Just, C.; Dean, J. C.; Singleton, J. T.; Longton, A. J.; Woodland, I.; Teasdale, A.; Gregertsen, B.; Else, H.; Athwal, M. S.; Tatterton, S.; Knott, J. M.; Thompson, N.; Smith, S. J. Org. Process Res. Dev. 2004, 8, 628. (i) Li, X.; Branum, S.; Russell, R. K.; Jiang, W.; Sui, Z. Org. Process Res. Dev. 2005, 9, 640. (j) Liu, J.; Cameron, M.; Hoerrner, S.; Williams, J. M.; McNamara, J. Org. Process Res. Dev. 2007, 11, 739. (k) Humphrey, C. E.; Furegati, M.; Laumen, K.; La Vecchia, L.; Leutert, T.; Müller-Hartwieg, J. C. D.; Vögtle, M. Org. Process Res. Dev. 2007, 11, 1069. (l) Wang, Y.; Papamichelakis, M.; Chew, W.; Sellstedt, J.; Noureldin, R.; Tadayon, S.; Daigneault, S.; Galante, R. J.; Sun, J. Org. Process Res. Dev. 2008, 12, 1253. (m) Maligres, P. E.; Humphrey, G. R.; Marcoux, J.-F.; Hillier, M. C.; Zhao, D.; Krska, S.; Grabowski, E. J. J. Org. Process Res. Dev. 2009, 13, 525. (n) Singh, H.; Gupta, N.; Kumar, P.; Dubey, S. K.; Sharma, P. K. Org. Process Res. Dev. 2009, 13, 870. (o) Ainge, D.; Booker, J. E. M.; Pedge, N.; Sinclair, R.; Sleigh, C.; Stefinović, M.; Vaz, L.-M.; Way, E. Org. Process Res. Dev. 2010, 14, 72. (p) Fray, J. M.; Gillmore, A. T.; Glossop, M. S.; McManus, D. J.; Moses, I. B.; Praquin, C. F. B.; Reeves, K. A.; Thompson, L. R. Org. Process Res. Dev. 2010, 14, 263. (q) Mao, Y.; Liu, Z.; Yang, X.; Xia, X.; Zhang, R.; Li, J.; Jiang, X.; Xie, K.; Zheng, J.; Zhang, H.; Suo, J.; Shen, J. Org. Process Res. Dev. 2012, 16, 1970. (r) Guz, N. R.; Leuser, H.; Goldman, E. Org. Process Res. Dev. 2013, 17, 1066. (s) Li, Z.; Fang, L.; Wang, J.; Dong, L.; Guo, Y.; Xie, Y. Org. Process Res. Dev. 2015, 19, 444. (22) Pivaloyl chloride: (a) Martinelli, M. J. J. Org. Chem. 1990, 55, 5065. (b) Beaulieu, P. L.; Gillard, J.; Bailey, M.; Beaulieu, C.; Duceppe, J.-S.; Lavallée, P.; Wernic, D. J. Org. Chem. 1999, 64, 6622. (c) Prashad, M.; Har, D.; Chen, L.; Kim, H.-Y.; Repič, O.; Blacklock, T. J. J. Org. Chem. 2002, 67, 6612. (d) Storace, L.; Anzalone, L.; Confalone, P. N.; Davis, W. P.; Fortunak, J. M.; Giangiordano, M.; Haley, J. J., Jr.; Kamholz, K.; Li, H.-Y.; Ma, P.; Nugent, W. A.; Parsons, R. L., Jr.; Sheeran, P. J.; Silverman, C. E.; Waltermire, R. E.; Wood, C. C. Org. Process Res. Dev. 2002, 6, 54. (e) Shieh, W.-C.; Chen, G.-P.; Xue, S.; McKenna, J.; Jiang, X.; Prasad, K.; Repič, O.; Straub, C.; Sharma, S. K. Org. Process Res. Dev. 2007, 11, 711. (f) Liu, Y.; Prashad, M.; Ciszewski, L.; Vargas, K.; Repič, O.; Blacklock, T. J. Org. Process Res. Dev. 2008, 12, 183. (g) Wang, Z.; Resnick, L. Tetrahedron 2008, 64, 6440. (h) Sasikala, C. H. V. A.; Padi, P. R.; Sunkara, V.; Ramayya, P.; Dubey, P. K.; Uppala, V. B. R.; Praveen, C. Org. Process Res. Dev. 2009, 13, 907. (i) Alimardanov, A.; Nikitenko, A.; Connolly, T. J.; Feigelson, G.; Chan, A. W.; Ding, Z.; Ghosh, M.; Shi, X.; Ren, J.; Hansen, E.; Farr, R.; MacEwan, M.; Tadayon, S.; Springer, D. M.; Kreft, A. F.; Ho, D. 172



Review

M.; Potoski, J. R. Org. Process Res. Dev. 2009, 13, 1161. (j) Xu, F.; Zacuto, M.; Yoshikawa, N.; Desmond, R.; Hoerrner, S.; Itoh, T.; Journet, M.; Humphrey, G. R.; Cowden, C.; Strotman, N.; Devine, P. J. Org. Chem. 2010, 75, 7829. (k) Tortoioli, S.; Marchal, D.; Kesselgruber, M.; Pabst, T.; Skranc, W.; Abele, S. Org. Process Res. Dev. 2014, 18, 1759. (23) Ethyl chloroformate: (a) Hirokawa, Y.; Horikawa, T.; Noguchi, H.; Yamamoto, K.; Kato, S. Org. Process Res. Dev. 2002, 6, 28. (b) Davulcu, A. H.; McLeod, D. D.; Li, J.; Katipally, K.; Littke, A.; Doubleday, W.; Xu, Z.; McConlogue, C. W.; Lai, C. J.; Gleeson, M.; Schwinden, M.; Parsons, R. L., Jr. J. Org. Chem. 2009, 74, 4068. (c) Berkessel, A.; Harnying, W.; Duangdee, N.; Neudörfl, J.-M.; Gröger, H. Org. Process Res. Dev. 2012, 16, 123. (d) Rai, B. P.; Tewari, N.; Nizar, H.; Prasad, M.; Joseph, S. Org. Process Res. Dev. 2014, 18, 662. (24) Isobutyl chloroformate: (a) Prashad, M.; Prasad, K.; Repič, O.; Blacklock, T. J.; Prikoszovich, W. Org. Process Res. Dev. 1999, 3, 409. (b) Andersen, P.; Ankersen, M.; Jessen, C. U.; Lehman, S. V. Org. Process Res. Dev. 2002, 6, 367. (c) Franzén, H. M.; Bessidskaia, G.; Abedi, V.; Nilsson, A.; Nilsson, M.; Olsson, L. Org. Process Res. Dev. 2002, 6, 788. (d) Lee, K. W.; Hwang, S. Y.; Kim, C. R.; Nam, D. H.; Chang, J. H.; Choi, S. C.; Choi, B. S.; Choi, H.-w.; Lee, K. K.; So, B.; Cho, S. W.; Shin, H. Org. Process Res. Dev. 2003, 7, 839. (e) Yee, N. K.; Nummy, L. J.; Frutos, R. P.; Song, J. J.; Napolitano, E.; Byrne, D. P.; Jones, P.-J.; Farina, V. Tetrahedron: Asymmetry 2003, 14, 3495. (f) Prashad, M.; Har, D.; Hu, B.; Kim, H.-Y.; Girgis, M. J.; Chaudhary, A.; Repič, O.; Blacklock, T. J.; Marterer, W. Org. Process Res. Dev. 2004, 8, 330. (g) Chen, J.; Corbin, S. P.; Holman, N. J. Org. Process Res. Dev. 2005, 9, 185. (h) Fan, X.; Song, Y.-L.; Long, Y.-Q. Org. Process Res. Dev. 2008, 12, 69. (i) Berwe, M.; Jöntgen, W.; Krüger, J.; CanchoGrande, Y.; Lampe, T.; Michels, M.; Paulsen, H.; Raddatz, S.; Weigand, S. Org. Process Res. Dev. 2011, 15, 1348. (j) Busacca, C. A.; Wei, X.; Haddad, N.; Kapadia, S.; Lorenz, J. C.; Saha, A. K.; Varsolona, R. J.; Berkenbusch, T.; Campbell, S. C.; Farina, V.; Feng, X.; Gonnella, N. C.; Grinberg, N.; Jones, P.-J.; Lee, H.; Li, Z.; Niemeier, O.; Samstag, W.; Sarvestani, M.; Schroeder, J.; Smoliga, J.; Spinelli, E. M.; Vitous, J.; Senanayake, C. H. Asian J. Org. Chem. 2012, 1, 80. (25) Mechanism of amide couplings via isobutyl chloroformate: (a) Chaudhary, A.; Girgis, M. J.; Prashad, M.; Hu, B.; Har, D.; Repič, O.; Blacklock, T. J. Org. Process Res. Dev. 2003, 7, 888. (b) Chaudhary, A.; Girgis, M. J.; Prashad, M.; Hu, B.; Har, D.; Repič, O.; Blacklock, T. J. Tetrahedron Lett. 2003, 44, 5543. (26) Boc anhydride: Patterson, D. E.; Powers, J. D.; LeBlanc, M.; Sharkey, T.; Boehler, E.; Irdam, E.; Osterhout, M. H. Org. Process Res. Dev. 2009, 13, 900. (27) Belleau, B.; Malek, G. J. Am. Chem. Soc. 1968, 90, 1651. (28) EEDQ: Ormerod, D.; Willemsens, B.; Mermans, R.; Langens, J.; Winderickx, G.; Kalindjian, S. B.; Buck, I. M.; McDonald, I. M. Org. Process Res. Dev. 2005, 9, 499. (29) Methanesulfonyl chloride: (a) Kobayashi, T.; Masui, Y.; Goto, Y.; Kitaura, Y.; Mizutani, T.; Matsumura, I.; Sugata, Y.; Ide, Y.; Takayama, M.; Takahashi, H.; Okuyama, A. Org. Process Res. Dev. 2004, 8, 744. (b) Norris, T.; VanAlsten, J.; Hubbs, S.; Ewing, M.; Cai, W.; Jorgensen, M. L.; Bordner, J.; Jensen, G. O. Org. Process Res. Dev. 2008, 12, 447. (30) Vaillancourt, V.; Cudahy, M. M.; Kreilein, M. M.; Jacobs, D. L.. Methanesulfonyl Chloride. e-EROS Encyclopedia of Reagents for Organic Synthesis; Wiley: New York, 2007. (31) p-Toluenesulfonyl chloride: (a) Campeau, L.-C.; Dolman, S. J.; Gauvreau, D.; Corley, E.; Liu, J.; Guidry, E. N.; Ouellet, S. G.; Steinhuebel, D.; Weisel, M.; O’Shea, P. D. Org. Process Res. Dev. 2011, 15, 1138. (b) Haddad, N.; Qu, B.; Lee, H.; Lorenz, J.; Varsolona, R.; Kapadia, S.; Sarvestani, M.; Feng, X.; Busacca, C. A.; Hebrault, D.; Rea, S.; Schellekens, L.; Senanayake, C. H. Org. Process Res. Dev. 2015, 19, 132. (32) (a) Shioiri, T.; Ninomiya, K.; Yamada, S. J. Am. Chem. Soc. 1972, 94, 6203. (b) Shioiri, T.; Yamada, S.-I. Chem. Pharm. Bull. 1974, 22, 849.

(33) (a) Wissmann, H.; Kleiner, H.-J. Angew. Chem., Int. Ed. Engl. 1980, 19, 133. (b) Wissmann, H. Phosphorus Sulfur Relat. Elem. 1987, 30, 645. (34) For a review of T3P chemistry: (a) Basavaprabhu; Vishwanatha, T. M.; Panguluri, N. R.; Sureshbabu, V. V. Synthesis 2013, 45, 1569. See also: (b) Schwarz, M. Synlett 2000, 1369. (c) García, A. L. L. Synlett 2007, 1328. (35) T3P: (a) Kammermeier, B.; Beck, G.; Holla, W.; Jacobi, D.; Napierski, B.; Jendralla, H. Chem. - Eur. J. 1996, 2, 307. (b) Dunn, P. J.; Hughes, M. L.; Searle, P. M.; Wood, A. S. Org. Process Res. Dev. 2003, 7, 244. (c) Paul, B. J.; Littler, B. J.; Jos, F.; Vogt, P. F. Org. Process Res. Dev. 2006, 10, 339. (d) Boggs, S. D.; Cobb, J. D.; Gudmundsson, K. S.; Jones, L. A.; Matsuoka, R. T.; Millar, A.; Patterson, D. E.; Samano, V.; Trone, M. D.; Xie, S.; Zhou, X.-m. Org. Process Res. Dev. 2007, 11, 539. (e) Kopach, M. E.; Singh, U. K.; Kobierski, M. E.; Trankle, W. G.; Murray, M. M.; Pietz, M. A.; Forst, M. B.; Stephenson, G. A.; Mancuso, V.; Giard, T.; Vanmarsenille, M.; DeFrance, T. Org. Process Res. Dev. 2009, 13, 209. (f) Butcher, K. J.; Denton, S. M.; Field, S. E.; Gillmore, A. T.; Harbottle, G. W.; Howard, R. M.; Laity, D. A.; Ngono, C. J.; Pibworth, B. A. Org. Process Res. Dev. 2011, 15, 1192. (g) Dunetz, J. R.; Xiang, Y.; Baldwin, A.; Ringling, J. Org. Lett. 2011, 13, 5048. (h) Dunetz, J. R.; Berliner, M. A.; Xiang, Y.; Houck, T. L.; Salingue, F. H.; Chao, W.; Yuandong, C.; Shenghua, W.; Huang, Y.; Farrand, D.; Boucher, S. J.; Damon, D. B.; Makowski, T. W.; Barrila, M. T.; Chen, R.; Martínez, I. Org. Process Res. Dev. 2012, 16, 1635. (i) Girardin, M.; Ouellet, S. G.; Gauvreau, D.; Moore, J. C.; Hughes, G.; Devine, P. N.; O’Shea, P. D.; Campeau, L.-C. Org. Process Res. Dev. 2013, 17, 61. (j) Shavnya, A.; Tao, Y.; Lilley, S. C.; Bahnck, K. B.; Munchhof, M. J.; Nematalla, A.; Waldo, M.; Bill, D. R. Org. Process Res. Dev. 2013, 17, 1510. (k) Lin, J.; Houpis, I. N.; Liu, R.; Wang, Y.; Zhang, J. Org. Process Res. Dev. 2014, 18, 205. (l) Boiteau, J.-G.; Rodeville, N.; Martin, C.; Tabet, S.; Moureou, C.; Muller, F.; Jetha, J.-C.; Cardinaud, I. Org. Process Res. Dev. 2015, 19, 646. (m) Kopach, M. E.; Heath, P. C.; Scherer, R. B.; Pietz, M. A.; Astleford, B. A.; McCauley, M. K.; Singh, U. K.; Wong, S. W.; Coppert, D. M.; Kerr, M. S.; Houghton, P. G. Org. Process Res. Dev. 2015, 19, 543. (36) Ethylmethylphosphinic anhydride: Jendralla, H.; Seuring, B.; Herchen, J.; Kulitzscher, B.; Wunner, J.; Stüber, W.; Koschinsky, R. Tetrahedron 1995, 51, 12047. [Note: This reference reports the use of “methyl-ethyl-phosphonic anhydride” for their amide coupling; however, this is not a known reagent for acid activation. SciFinder has since corrected this reagent to ethylmethylphosphinic anhydride, a known coupling reagent, and we have done the same for this review.]. (37) CDI: (a) Pierce, M. E.; Harris, G. D.; Islam, Q.; Radesca, L. A.; Storace, L.; Waltermire, R. E.; Wat, E.; Jadhav, P. K.; Emmett, G. C. J. Org. Chem. 1996, 61, 444. (b) Perrault, W. R.; Shephard, K. P.; LaPean, L. A.; Krook, M. A.; Dobrowolski, P. J.; Lyster, M. A.; McMillan, M. W.; Knoechel, D. J.; Evenson, G. N.; Watt, W.; Pearlman, B. A. Org. Process Res. Dev. 1997, 1, 106. (c) Dale, D. J.; Dunn, P. J.; Golightly, C.; Hughes, M. L.; Levett, P. C.; Pearce, A. K.; Searle, P. M.; Ward, G.; Wood, A. S. Org. Process Res. Dev. 2000, 4, 17. (d) Coutts, L. D.; Geiss, W. B.; Gregg, B. T.; Helle, M. A.; King, C.-H. R.; Itov, Z.; Mateo, M. E.; Meckler, H.; Zettler, M. W.; Knutson, J. C. Org. Process Res. Dev. 2002, 6, 246. (e) Dale, D. J.; Draper, J.; Dunn, P. J.; Hughes, M. L.; Hussain, F.; Levett, P. C.; Ward, G. B.; Wood, A. S. Org. Process Res. Dev. 2002, 6, 767. (f) Stuk, T. L.; Assink, B. K.; Bates, R. C., Jr.; Erdman, D. T.; Fedij, V.; Jennings, S. M.; Lassig, J. A.; Smith, R. J.; Smith, T. L. Org. Process Res. Dev. 2003, 7, 851. (g) Beaudin, J.; Bourassa, D. E.; Bowles, P.; Castaldi, M. J.; Clay, R.; Couturier, M. A.; Karrick, G.; Makowski, T. W.; McDermott, R. E.; Meltz, C. N.; Meltz, M.; Phillips, J. E.; Ragan, J. A.; Ripin, D. H. B.; Singer, R. A.; Tucker, J. L.; Wei, L. Org. Process Res. Dev. 2003, 7, 873. (h) Chen, C.-y.; Dagneau, P.; Grabowski, E. J. J.; Oballa, R.; O’Shea, P.; Prasit, P.; Robichaud, J.; Tillyer, R.; Wang, X. J. Org. Chem. 2003, 68, 2633. (i) Bänziger, M.; Cercus, J.; Hirt, H.; Laumen, K.; Malan, C.; Spindler, F.; Struber, F.; Troxler, T. Tetrahedron: Asymmetry 2003, 14, 3469. (j) Liu, H.; Kerdesky, F. A.; Black, L. A.; Fitzgerald, M.; Henry, R.; Esbenshade, T. A.; Hancock, A. A.; Bennani, Y. L. J. Org. Chem. 2004, 69, 192. (k) Magnus, N. A.; Aikins, J. A.; Cronin, J. S.; Diseroad, W. 173



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D.; Hargis, A. D.; LeTourneau, M. E.; Parker, B. E.; Reutzel-Edens, S. M.; Schafer, J. P.; Staszak, M. A.; Stephenson, G. A.; Tameze, S. L.; Zollars, L. M. H. Org. Process Res. Dev. 2005, 9, 621. (l) Ashcroft, C. P.; Challenger, S.; Clifford, D.; Derrick, A. M.; Hajikarimian, Y.; Slucock, K.; Silk, T. V.; Thomson, N. M.; Williams, J. R. Org. Process Res. Dev. 2005, 9, 663. (m) Albaneze-Walker, J.; Murry, J. A.; Soheili, A.; Ceglia, S.; Springfield, S. A.; Bazaral, C.; Dormer, P. G.; Hughes, D. L. Tetrahedron 2005, 61, 6330. (n) Scott, R. W.; Neville, S. N.; Urbina, A.; Camp, D.; Stankovic, N. Org. Process Res. Dev. 2006, 10, 296. (o) Challenger, S.; Dessi, Y.; Fox, D. E.; Hesmondhalgh, L. C.; Pascal, P.; Pettman, A. J.; Smith, J. D. Org. Process Res. Dev. 2008, 12, 575. (p) Kuethe, J. T.; Childers, K. G.; Humphrey, G. R.; Journet, M.; Peng, Z. Org. Process Res. Dev. 2008, 12, 1201. (q) Weisenburger, G. A.; Anderson, D. K.; Clark, J. D.; Edney, A. D.; Karbin, P. S.; Gallagher, D. J.; Knable, C. M.; Pietz, M. A. Org. Process Res. Dev. 2009, 13, 60. (r) Thiel, O. R.; Achmatowicz, M.; Bernard, C.; Wheeler, P.; Savarin, C.; Correll, T. L.; Kasparian, A.; Allgeier, A.; Bartberger, M. D.; Tan, H.; Larsen, R. D. Org. Process Res. Dev. 2009, 13, 230. (s) Kuethe, J. T.; Childers, K. G.; Peng, Z.; Journet, M.; Humphrey, G. R.; Vickery, T.; Bachert, D.; Lam, T. T. Org. Process Res. Dev. 2009, 13, 576. (t) Bellingham, R.; Buswell, A. M.; Choudary, B. M.; Gordon, A. H.; Moore, S. O.; Peterson, M.; Sasse, M.; Shamji, A.; Urquhart, M. W. J. Org. Process Res. Dev. 2010, 14, 1254. (u) Bradley, P. A.; Carroll, R. J.; Lecouturier, Y. C.; Moore, R.; Noeureuil, P.; Patel, B.; Snow, J.; Wheeler, S. Org. Process Res. Dev. 2010, 14, 1326. (v) Deng, X.; Liang, J. T.; Peterson, M.; Rynberg, R.; Cheung, E.; Mani, N. S. J. Org. Chem. 2010, 75, 1940. (w) Sieser, J. E.; Singer, R. A.; McKinley, J. D.; Bourassa, D. E.; Teixeira, J. J.; Long, J. Org. Process Res. Dev. 2011, 15, 1328. (x) Yoshida, S.; Kasai, M.; Kimura, T.; Akiba, T.; Takahashi, T.; Sakamoto, S. Org. Process Res. Dev. 2012, 16, 654. (y) Li, W.; Gao, J. J.; Lorenz, J. C.; Xu, J.; Johnson, J.; Ma, S.; Lee, H.; Grinberg, N.; Busacca, C. A.; Lu, B.; Senanayake, C. H. Org. Process Res. Dev. 2012, 16, 836. (z) Hu, B.; Song, Q.; Xu, Y. Org. Process Res. Dev. 2012, 16, 1552. (aa) Alorati, A. D.; Gibb, A. D.; Mullens, P. R.; Stewart, G. W. Org. Process Res. Dev. 2012, 16, 1947. (ab) Content, S.; Dupont, T.; Fédou, N. M.; Smith, J. D.; Twiddle, S. J. R. Org. Process Res. Dev. 2013, 17, 193. (ac) Neelakandan, K.; Manikandan, H.; Santosha, N.; Prabhakaran, B. Org. Process Res. Dev. 2013, 17, 981. (ad) Betti, M.; Genesio, E.; Panico, A.; Coccone, S. S.; Wiedenau, P. Org. Process Res. Dev. 2013, 17, 1042. (ae) Andersen, S. M.; Aurell, C.-J.; Zetterberg, F.; Bollmark, M.; Ehrl, R.; Schuisky, P.; Witt, A. Org. Process Res. Dev. 2013, 17, 1543. (af) Kallemeyn, J. M.; Ku, Y.-Y.; Mulhern, M. M.; Bishop, R.; Pal, A.; Jacob, L. Org. Process Res. Dev. 2014, 18, 191. (ag) Chung, C. K.; Bulger, P. G.; Kosjek, B.; Belyk, K. M.; Rivera, N.; Scott, M. E.; Humphrey, G. R.; Limanto, J.; Bachert, D. C.; Emerson, K. M. Org. Process Res. Dev. 2014, 18, 215. (ah) Betti, M.; Genesio, E.; Marconi, G.; Coccone, S. S.; Wiedenau, P. Org. Process Res. Dev. 2014, 18, 699. (38) Vaidyanathan, R.; Kalthod, V. G.; Ngo, D. P.; Manley, J. M.; Lapekas, S. P. J. Org. Chem. 2004, 69, 2565. (39) Engstrom, K. M.; Sheikh, A.; Ho, R.; Miller, R. W. Org. Process Res. Dev. 2014, 18, 488. (40) Sheehan, J. C.; Hess, G. P. J. Am. Chem. Soc. 1955, 77, 1067. (41) (a) Williams, A.; Ibrahim, I. T. Chem. Rev. 1981, 81, 589. (b) Mikolajczyk, M.; Kielbasinski, P. Tetrahedron 1981, 37, 233. (42) König, W.; Geiger, R. Chem. Ber. 1970, 103, 788. (43) DCC: (a) Cvetovich, R. J.; Chartrain, M.; Hartner, F. W.; Roberge, C.; Amato, J. S.; Grabowski, E. J. J. J. Org. Chem. 1996, 61, 6575. (b) D’Andrea, S. V.; Bonner, D.; Bronson, J. J.; Clark, J.; Denbleyker, K.; Fung-Tomc, J.; Hoeft, S. E.; Hudyma, T. W.; Matiskella, J. D.; Miller, R. F.; Misco, P. F.; Pucci, M.; Sterzycki, R.; Tsai, Y.; Ueda, Y.; Wichtowski, J. A.; Singh, J.; Kissick, T. P.; North, J. T.; Pullockaran, A.; Humora, M.; Boyhan, B.; Vu, T.; Fritz, A.; Heikes, J.; Fox, R.; Godfrey, J. D.; Perrone, R.; Kaplan, M.; Kronenthal, D.; Mueller, R. H. Tetrahedron 2000, 56, 5687. (c) Hilpert, H. Tetrahedron 2001, 57, 7675. (d) Singh, J.; Denzel, T. W.; Fox, R.; Kissick, T. P.; Herter, R.; Wurdinger, J.; Schierling, P.; Papaioannou, C. G.; Moniot, J. L.; Mueller, R. H.; Cimarusti, C. M. Org. Process Res. Dev. 2002, 6, 863. (e) Cohen, J. H.; Bos, M. E.; Cesco-Cancian, S.; Harris, B. D.;

Hortenstine, J. T.; Justus, M.; Maryanoff, C. A.; Mills, J.; Muller, S.; Roessler, A.; Scott, L.; Sorgi, K. L.; Villani, F. J.; Webster, R. R. H.; Weh, C. Org. Process Res. Dev. 2003, 7, 866. (f) Zheng, N.; Armstrong, J. D.; Eng, K. K.; Keller, J.; Liu, T.; Purick, R.; Lynch, J.; Hartner, F. W.; Volante, R. P. Tetrahedron: Asymmetry 2003, 14, 3435. (g) Sjövall, S.; Hansen, L.; Granquist, B. Org. Process Res. Dev. 2004, 8, 802. (h) Srinivas, K.; Srinivasan, N.; Krishna, M. R.; Reddy, C. R.; Arunagiri, M.; Lalitha, R.; Reddy, K. S. R.; Reddy, B. S.; Reddy, G. M.; Reddy, P. P.; Kumar, M. K.; Reddy, M. S. Org. Process Res. Dev. 2004, 8, 952. (i) Wennerberg, J.; Björk, A.; Fristedt, T.; Granquist, B.; Jansson, K.; Thuvesson, I. Org. Process Res. Dev. 2007, 11, 674. (j) Kotagiri, V. K.; Suthrapu, S.; Reddy, J. M.; Rao, C. P.; Bollugoddu, V.; Bhattacharya, A.; Bandichhor, R. Org. Process Res. Dev. 2007, 11, 910. (k) Goverdhan, G.; Reddy, A. R.; Sampath, A.; Srinivas, K.; Himabindu, V.; Reddy, G. M. Org. Process Res. Dev. 2009, 13, 67. (44) DIC: (a) Clark, J. D.; Anderson, D. K.; Banaszak, D. V.; Brown, D. B.; Czyzewski, A. M.; Edeny, A. D.; Forouzi, P. S.; Gallagher, D. J.; Iskos, V. H.; Kleine, H. P.; Knable, C. M.; Lantz, M. K.; Lapack, M. A.; Moore, C. M. V.; Muellner, F. W.; Murphy, J. B.; Orihuela, C. A.; Pietz, M. A.; Rogers, T. E.; Ruminski, P. G.; Santhanam, H. K.; Schilke, T. C.; Shah, A. S.; Sheikh, A. Y.; Weisenburger, G. A.; Wise, B. E. Org. Process Res. Dev. 2009, 13, 1088. (b) Affouard, C.; Crockett, R. D.; Diker, K.; Farrell, R. P.; Gorins, G.; Huckins, J. R.; Caille, S. Org. Process Res. Dev. 2015, 19, 476. (45) Goyal, N. Synlett 2010, 335. (46) EDC: (a) Chung, J. Y. L.; Hughes, D. L.; Zhao, D.; Song, Z.; Mathre, D. J.; Ho, G.-J.; McNamara, J. M.; Douglas, A. W.; Reamer, R. A.; Tsay, F.-R.; Varsolona, R.; McCauley, J.; Grabowski, E. J. J.; Reider, P. J. J. Org. Chem. 1996, 61, 215. (b) Bold, G.; Fässler, A.; Capraro, H.G.; Cozens, R.; Klimkait, T.; Lazdins, J.; Mestan, J.; Poncioni, B.; Rösel, J.; Stover, D.; Tintelnot-Blomley, M.; Acemoglu, F.; Beck, W.; Boss, E.; Eschbach, M.; Hürlimann, T.; Masso, E.; Roussel, S.; UcciStoll, K.; Wyss, D.; Lang, M. J. Med. Chem. 1998, 41, 3387. (c) Mase, T.; Houpis, I. N.; Akao, A.; Dorziotis, I.; Emerson, K.; Hoang, T.; Iida, T.; Itoh, T.; Kamei, K.; Kato, S.; Kato, Y.; Kawasaki, M.; Lang, F.; Lee, J.; Lynch, J.; Maligres, P.; Molina, A.; Nemoto, T.; Okada, S.; Reamer, R.; Song, J. Z.; Tschaen, D.; Wada, T.; Zewge, D.; Volante, R. P.; Reider, P. J.; Tomimoto, K. J. Org. Chem. 2001, 66, 6775. (d) Ito, T.; Ikemoto, T.; Isogami, Y.; Wada, H.; Sera, M.; Mizuno, Y.; Wakimasu, M. Org. Process Res. Dev. 2002, 6, 238. (e) Xu, Z.; Singh, J.; Schwinden, M. D.; Zheng, B.; Kissick, T. P.; Patel, B.; Humora, M. J.; Quiroz, F.; Dong, L.; Hsieh, D.-M.; Heikes, J. E.; Pudipeddi, M.; Lindrud, M. D.; Srivastava, S. K.; Kronenthal, D. R.; Mueller, R. H. Org. Process Res. Dev. 2002, 6, 323. (f) Couturier, M.; Tucker, J. L.; Andresen, B. M.; DeVries, K. M.; Vanderplas, B. C.; Ito, F. Tetrahedron: Asymmetry 2003, 14, 3517. (g) Chung, J. Y. L.; Cvetovich, R. J.; Tsay, F.-R.; Dormer, P. G.; DiMichele, L.; Mathre, D. J.; Chilenski, J. R.; Mao, B.; Wenslow, R. J. Org. Chem. 2003, 68, 8838. (h) Ashcroft, C. P.; Challenger, S.; Derrick, A. M.; Storey, R.; Thomson, N. M. Org. Process Res. Dev. 2003, 7, 362. (i) Nelson, T. D.; LeBlond, C. R.; Frantz, D. E.; Matty, L.; Mitten, J. V.; Weaver, D. G.; Moore, J. C.; Kim, J. M.; Boyd, R.; Kim, P.-Y.; Gbewonyo, K.; Brower, M.; Sturr, M.; McLaughlin, K.; McMasters, D. R.; Kress, M. H.; McNamara, J. M.; Dolling, U. H. J. Org. Chem. 2004, 69, 3620. (j) Maruyama, N.; Shimizu, H.; Sugiyama, T.; Watanabe, M.; Makino, M.; Kato, M.; Shimizu, M. Org. Process Res. Dev. 2004, 8, 883. (k) Hansen, K. B.; Balsells, J.; Dreher, S.; Hsiao, Y.; Kubryk, M.; Palucki, M.; Rivera, N.; Steinhuebel, D.; Armstrong, J. D.; Askin, D.; Grabowski, E. J. J. Org. Process Res. Dev. 2005, 9, 634. (l) Angelaud, R.; Zhong, Y.-L.; Maligres, P.; Lee, J.; Askin, D. J. Org. Chem. 2005, 70, 1949. (m) Aikins, J. A.; Haurez, M.; Rizzo, J. R.; Van Hoeck, J.-P.; Brione, W.; Kestemont, J.-P.; Stevens, C.; Lemair, X.; Stephenson, G. A.; Marlot, E.; Forst, M.; Houpis, I. N. J. Org. Chem. 2005, 70, 4695. (n) Yee, N. K.; Farina, V.; Houpis, I. N.; Haddad, N.; Frutos, R. P.; Gallou, F.; Wang, X.-j.; Wei, X.; Simpson, R. D.; Feng, X.; Fuchs, V.; Xu, Y.; Tan, J.; Zhang, L.; Xu, J.; Smith-Keenan, L. L.; Vitous, J.; Ridges, M. D.; Spinelli, E. M.; Johnson, M.; Donsbach, K.; Nicola, T.; Brenner, M.; Winter, E.; Kreye, P.; Samstag, W. J. Org. Chem. 2006, 71, 7133. (o) Benoit, G.-E.; Carey, J. S.; Chapman, A. M.; Chima, R.; Hussain, N.; Popkin, M. E.; Roux, G.; Tavassoli, B.; 174



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Vaxelaire, C.; Webb, M. R.; Whatrup, D. Org. Process Res. Dev. 2008, 12, 88. (p) Nikitenko, A.; Alimardanov, A.; Afragola, J.; Schmid, J.; Kristofova, L.; Evrard, D.; Hatzenbuhler, N. T.; Marathias, V.; Stack, G.; Lenicek, S.; Potoski, J. Org. Process Res. Dev. 2009, 13, 91. (q) Abbas, S.; Ferris, L.; Norton, A. K.; Powell, L.; Robinson, G. E.; Siedlecki, P.; Southworth, R. J.; Stark, A.; Williams, E. G. Org. Process Res. Dev. 2008, 12, 202. (r) Becker, C. L.; Engstrom, K. M.; Kerdesky, F. A.; Tolle, J. C.; Wagaw, S. H.; Wang, W. Org. Process Res. Dev. 2008, 12, 1114. (s) Pu, Y. J.; Vaid, R. K.; Boini, S. K.; Towsley, R. W.; Doecke, C. W.; Mitchell, D. Org. Process Res. Dev. 2009, 13, 310. (t) Shu, C.; Zeng, X.; Hao, M.-H.; Wei, X.; Yee, N. K.; Busacca, C. A.; Han, Z.; Farina, V.; Senanayake, C. H. Org. Lett. 2008, 10, 1303. (u) Wilmouth, S.; Bufferne-Perret, C.; Flouzat, C.; Humblot, G.; Ray, C.; Simbille, N. Tetrahedron 2009, 65, 2689. (v) Molinaro, C.; Gauvreau, D.; Hughes, G.; Lau, S.; Lauzon, S.; Angelaud, R.; O’Shea, P. D.; Janey, J.; Palucki, M.; Hoerrner, S. R.; Raab, C. E.; Sidler, R. R.; Belley, M.; Han, Y. J. Org. Chem. 2009, 74, 6863. (w) Ohta, C.; Kuwabe, S.-i.; Shiraishi, T.; Shinohara, I.; Araki, H.; Sakuyama, S.; Makihara, T.; Kawanaka, Y.; Ohuchida, S.; Seko, T. J. Org. Chem. 2009, 74, 8298. (x) Wang, H.; Matsuhashi, H.; Doan, B. D.; Goodman, S. N.; Ouyang, X.; Clark, W. M. Tetrahedron 2009, 65, 6291. (y) Menzel, K.; Machrouhi, F.; Bodenstein, M.; Alorati, A.; Cowden, C.; Gibson, A. W.; Bishop, B.; Ikemoto, N.; Nelson, T. D.; Kress, M. H.; Frantz, D. E. Org. Process Res. Dev. 2009, 13, 519. (z) Broeders, F.; Defrère, L.; Deltent, M.-F.; Driessens, F.; Gilson, F.; Grooters, L.; Ikonomakos, X.; Limauge, F.; Sergeef, E.; Verstraeten, N. Org. Process Res. Dev. 2009, 13, 442. (aa) Savage, S. A.; Jones, G. S.; Kolotuchin, S.; Ramrattan, S. A.; Vu, T.; Waltermire, R. E. Org. Process Res. Dev. 2009, 13, 1169. (ab) Lorenz, J. C.; Busacca, C. A.; Feng, X.; Grinberg, N.; Haddad, N.; Johnson, J.; Kapadia, S.; Lee, H.; Saha, A.; Sarvestani, M.; Spinelli, E. M.; Varsolona, R.; Wei, X.; Zeng, X.; Senanayake, C. H. J. Org. Chem. 2010, 75, 1155. (ac) Yoshikawa, N.; Xu, F.; Arredondo, J. D.; Itoh, T. Org. Process Res. Dev. 2011, 15, 824. (ad) Song, Z. J.; Tellers, D. M.; Journet, M.; Kuethe, J. T.; Lieberman, D.; Humphrey, G.; Zhang, F.; Peng, Z.; Waters, M. S.; Zewge, D.; Nolting, A.; Zhao, D.; Reamer, R. A.; Dormer, P. G.; Belyk, K. M.; Davies, I. W.; Devine, P. N.; Tschaen, D. M. J. Org. Chem. 2011, 76, 7804. (ae) Zhu, J.; Razler, T. M.; Xu, Z.; Conlon, D. A.; Sortore, E. W.; Fritz, A. W.; Demerzhan, R.; Sweeney, J. T. Org. Process Res. Dev. 2011, 15, 438. (af) Crawford, J. B.; Chen, G.; Carpenter, B.; Wilson, T.; Ji, J.; Skerlj, R. T.; Bridger, G. J. Org. Process Res. Dev. 2012, 16, 109. (ag) Ruck, R. T.; Huffman, M. A.; Stewart, G. W.; Cleator, E.; Kandur, W. V.; Kim, M. M.; Zhao, D. Org. Process Res. Dev. 2012, 16, 1329. (ah) Lafrance, D.; Caron, S. Org. Process Res. Dev. 2012, 16, 409. (ai) Shi, Z.; Kiau, S.; Lobben, P.; Hynes, J.; Wu, H.; Parlanti, L.; Discordia, R.; Doubleday, W. W.; Leftheris, K.; Dyckman, A. J.; Wrobleski, S. T.; Dambalas, K.; Tummala, S.; Leung, S.; Lo, E. Org. Process Res. Dev. 2012, 16, 1618. (aj) Shu, L.; Gu, C.; Dong, Y.; Brinkman, R. Org. Process Res. Dev. 2012, 16, 1940. (ak) Liu, Y.; Prashad, M.; Shieh, W.-C. Org. Process Res. Dev. 2014, 18, 239. (al) Liu, Y.; Prashad, M.; Shieh, W.-C. Org. Process Res. Dev. 2014, 18, 239. (am) Teleha, C. A.; Branum, S.; Zhang, Y.; Reuman, M. E.; Van Der Steen, L.; Verbeek, M.; Fawzy, N.; Leo, G. C.; Kang, F.-A.; Cai, C.; Kolpak, M.; Beauchamp, D. A.; Wall, M. J.; Russell, R. K.; Sui, Z.; Vanbaelen, H. Org. Process Res. Dev. 2014, 18, 1622. (an) Teleha, C. A.; Branum, S.; Zhang, Y.; Reuman, M. E.; Van Der Steen, L.; Verbeek, M.; Fawzy, N.; Leo, G. C.; Winters, M. P.; Kang, F.-A.; Kolpak, M.; Beauchamp, D. A.; Lanter, J. C.; Russell, R. K.; Sui, Z.; Vanbaelen, H. Org. Process Res. Dev. 2014, 18, 1630. (ao) Funel, J.-A.; Brodbeck, S.; Guggisberg, Y.; Litjens, R.; Seidel, T.; Struijk, M.; Abele, S. Org. Process Res. Dev. 2014, 18, 1674. (ap) Chen, J.; Chen, T.; Hu, Q.; Püntener, K.; Ren, Y.; She, J.; Du, Z.; Scalone, M. Org. Process Res. Dev. 2014, 18, 1702. (aq) Mangion, I. K.; Chen, C.; Li, H.; Maligres, P.; Chen, Y.; Christensen, M.; Cohen, R.; Jeon, I.; Klapars, A.; Krska, S.; Nguyen, H.; Reamer, R. A.; Sherry, B. D.; Zavialov, I. Org. Lett. 2014, 16, 2310. (ar) Littler, B. J.; Aizenberg, M.; Ambhaikar, N. B.; Blythe, T. A.; Curran, T. T.; Dvornikovs, V.; Jung, Y. C.; Jurkauskas, V.; Lee, E. C.; Looker, A. R.; Luong, H.; Martinot, T. A.; Miller, D. B.; Neubert-Langille, B. J.; Otten, P. A.; Rose, P. J.; Ruggiero, P. L. Org. Process Res. Dev. 2015, 19, 270.

(47) (a) Castro, B.; Dormoy, J. R. Bull. Soc. Chim. Fr. 1973, 12, 3359. (b) Castro, B.; Dormoy, J. R. Tetrahedron Lett. 1973, 14, 3243. (c) Castro, B.; Dormoy, J. R.; Evin, G.; Selve, C. Tetrahedron Lett. 1975, 16, 1219. (d) Castro, B.; Dormoy, J. R.; Evin, G.; Selve, C. J. Chem. Res. (S) 1977, 182. (48) (a) Coste, J.; Le-Nguyen, D.; Castro, B. Tetrahedron Lett. 1990, 31, 205. (b) Wang, W.; McMurray, J. S. Tetrahedron Lett. 1999, 40, 2501. (49) HOBt is potentially explosive in its anhydrous form (Class 1 explosive category), which has led to retrictions for its shipping. See: Wehrstedt, K. D.; Wandrey, P. A.; Heitkamp, D. J. Hazard. Mater. 2005, 126, 1. (50) BOP: Ishikawa, M.; Tsushima, M.; Kubota, D.; Yanagisawa, Y.; Hiraiwa, Y.; Kojima, Y.; Ajito, K.; Anzai, N. Org. Process Res. Dev. 2008, 12, 596. (51) (a) Dourtoglou, V.; Ziegler, J.-C.; Gross, B. Tetrahedron Lett. 1978, 19, 1269. (b) Dourtoglou, V.; Ziegler, J.-C.; Gross, B. Synthesis 1984, 572. (c) Carpino, L. A.; Imazumi, H.; El-Faham, A.; Ferrer, F. J.; Zhang, C.; Lee, Y.; Foxman, B. M.; Henklein, P.; Hanay, C.; Mügge, C.; Wenschuh, H.; Klose, J.; Beyermann, M.; Bienert, M. Angew. Chem., Int. Ed. 2002, 41, 441. (52) Knorr, R.; Trzeciak, A.; Bannwarth, W.; Gillessen, D. Tetrahedron Lett. 1989, 30, 1927. (53) N,N,N′,N′-tetramethylurea has been reported to be cytotoxic. Coste, D. L.-N.; Castro, B. Tetrahedron Lett. 1990, 31, 205 and references therein.. (54) HBTU: Remarchuk, T.; St-Jean, F.; Carrera, D.; Savage, S.; Yajima, H.; Wong, B.; Babu, S.; Deese, A.; Stults, J.; Dong, M. W.; Askin, D.; Lane, J. W.; Spencer, K. L. Org. Process Res. Dev. 2014, 18, 1652. (55) Carpino, L. A. J. Am. Chem. Soc. 1993, 115, 4397. (56) Carpino, L. A.; El-Faham, A.; Albericio, F. Tetrahedron Lett. 1994, 35, 2279. (57) HATU: (a) Andrews, D. M.; Arnould, J.-C.; Boutron, P.; Délouvrie, B.; Delvare, C.; Foote, K. M.; Hamon, A.; Harris, C. S.; Lambert-van der Brempt, C.; Lamorlette, M.; Matusiak, Z. M. Tetrahedron 2009, 65, 5805. (b) O’Shea, P. D.; Chen, C.-y.; Gauvreau, D.; Gosselin, F.; Hughes, G.; Nadeau, C.; Volante, R. P. J. Org. Chem. 2009, 74, 1605. (c) Fei, Z.; Kong, W.; Wang, H.; Peng, J.; Sun, F.; Yin, Y.; Bajwa, J.; Jiang, X. Org. Process Res. Dev. 2012, 16, 1436. (d) Roemmele, R. C.; Christie, M. A. Org. Process Res. Dev. 2013, 17, 422. (e) Pikul, S.; Cheng, H.; Cheng, A.; Huang, C. D.; Ke, A.; Kuo, L.; Thompson, A.; Wilder, S. Org. Process Res. Dev. 2013, 17, 907. (58) TBTU: (a) Faucher, A.-M.; Bailey, M. D.; Beaulieu, P. L.; Brochu, C.; Duceppe, J.-S.; Ferland, J.-M.; Ghiro, E.; Gorys, V.; Halmos, T.; Kawai, S. H.; Poirier, M.; Simoneau, B.; Tsantrizos, Y. S.; Llinàs-Brunet, M. Org. Lett. 2004, 6, 2901. (b) Karlsson, S.; Sörensen, J. H. Org. Process Res. Dev. 2012, 16, 586. (59) Cyanuric chloride: Rayle, H. L.; Fellmeth, L. Org. Process Res. Dev. 1999, 3, 172. (60) Kamiński, Z. J. Tetrahedron Lett. 1985, 26, 2901. (61) Garrett, C. E.; Jiang, X.; Prasad, K.; Repič, O. Tetrahedron Lett. 2002, 43, 4161. (62) CDMT: (a) Barnett, C. J.; Wilson, T. M.; Kobierski, M. E. Org. Process Res. Dev. 1999, 3, 184. (b) Walker, A. J.; Adolph, S.; Connell, R. B.; Laue, K.; Roeder, M.; Rueggeberg, C. J.; Hahn, D. U.; Voegtli, K.; Watson, J. Org. Process Res. Dev. 2010, 14, 85. (c) Villhauer, E. B.; Shieh, W.-C.; Du, Z.; Vargas, K.; Ciszewski, L.; Lu, Y.; Girgis, M.; Lin, M.; Prashad, M. Tetrahedron 2009, 65, 9067. (d) Kallman, N. J.; Liu, C.; Yates, M. H.; Linder, R. J.; Ruble, J. C.; Kogut, E. F.; Patterson, L. E.; Laird, D. L. T.; Hansen, M. M. Org. Process Res. Dev. 2014, 18, 501. (e) Kallman, N. J.; Liu, C.; Yates, M. H.; Linder, R. J.; Ruble, J. C.; Kogut, E. F.; Patterson, L. E.; Laird, D. L. T.; Hansen, M. M. Org. Process Res. Dev. 2014, 18, 501. (63) Kunishima, M.; Kawachi, C.; Iwasaki, F.; Terao, K.; Tani, S. Tetrahedron Lett. 1999, 40, 5327. (64) Kunishima, M.; Kawachi, C.; Monta, J.; Terao, K.; Iwasaki, F.; Tani, S. Tetrahedron 1999, 55, 13159. (65) Zheng, H.; Hall, D. G. Aldrichimica Acta 2014, 47, 41. 175



Review

(66) (a) Pelter, A.; Levitt, T. E.; Nelsoni, P. Tetrahedron 1970, 26, 1539. (b) Pelter, A.; Levitt, T. E. Tetrahedron 1970, 26, 1545. (c) Tani, J.; Oine, T.; Inoue, I. Synthesis 1975, 714. (d) Collum, D. B.; Chen, S.C.; Ganem, B. J. Org. Chem. 1978, 43, 4393. (e) Trapani, G.; Reho, A.; Latrofa, A. Synthesis 1983, 1013. (67) Carlson, R.; Lundstedt, T.; Nordahl, A.; Prochazka, M. Acta Chem. Scand. 1986, 40, 522. (68) (a) Ishihara, K.; Ohara, S.; Yamamoto, H. J. Org. Chem. 1996, 61, 4196. (b) Ishihara, K.; Kondo, S.; Yamamoto, H. Synlett 2001, 1371. (69) Ishihara, K.; Ohara, S.; Yamamoto, H. Org. Synth. 2003, 79, 176. (70) Tang, P. Org. Synth. 2005, 81, 262. (71) Reddy, J. M.; Kumar, K. V.; Raju, V.; Bhaskar, B. V.; Himabindu, V.; Bhattacharya, A.; Sundaram, V.; Banerjee, R.; Reddy, G. M.; Bandichhor, R. Synth. Commun. 2008, 38, 2138. (72) Al-Zoubi, R. M.; Marion, O.; Hall, D. G. Angew. Chem., Int. Ed. 2008, 47, 2876. (73) Gernigon, N.; Al-Zoubi, R. M.; Hall, D. G. J. Org. Chem. 2012, 77, 8386. (74) (a) Ishihara, K.; Ohara, S.; Yamamoto, H. Macromolecules 2000, 33, 3511. (b) Arnold, K.; Davies, B.; Giles, R. L.; Grosjean, C.; Smith, G. E.; Whiting, A. Adv. Synth. Catal. 2006, 348, 813. (75) (a) Georgiou, I.; Ilyashenko, G.; Whiting, A. Acc. Chem. Res. 2009, 42, 756. (b) Arnold, K.; Batsanov, A. S.; Davies, B.; Whiting, A. Green Chem. 2008, 10, 124. (76) (a) Lanigan, R. M.; Starkov, P.; Sheppard, T. D. J. Org. Chem. 2013, 78, 4512. (b) Karaluka, V.; Lanigan, R. M.; Murray, P. M.; Badland, M.; Sheppard, T. D. Org. Biomol. Chem. 2015, 13, 10888. (77) Starkov, P.; Sheppard, T. D. Org. Biomol. Chem. 2011, 9, 1320. (78) Maki, T.; Ishihara, K.; Yamamoto, H. Tetrahedron 2007, 63, 8645. (79) Maki, T.; Ishihara, K.; Yamamoto, H. Org. Lett. 2006, 8, 1431. (80) (a) National Pesticide Information Centre (2001). http://npic. orst.edu/factsheets/boricgen.pdf (accessed June 26, 2015). (b) Heindel, J. J.; Price, C. J.; Field, E. A.; Marr, M. C.; Myers, C. B.; Morrissey, R. E.; Schwetz, B. A. Fundam. Appl. Toxicol. 1992, 18, 266. (c) Price, C. J.; Marr, M. C.; Myers, C. B.; Seely, J. C.; Heindel, J. J.; Schwetz, B. A. Fundam. Appl. Toxicol. 1996, 34, 176. (81) Boric Acid, Substances of Very High Concern (SVHC) Support Document http://echa.europa.eu/doc/candidate_list/svhc_supdoc_ boric_acid_publication.pdf (accessed June 26, 2015). (82) Ishihara, K.; Yamamoto, H. Eur. J. Org. Chem. 1999, 527. (83) Boric acid: (a) Anderson, J. E.; Davis, R.; Fitzgerald, R. N.; Haberman, J. M. Synth. Commun. 2006, 36, 2129. (b) Mylavarapu, R. K.; GCM, K.; Kolla, N.; Veeramalla, R.; Koilkonda, P.; Bhattacharya, A.; Bandichhor. Org. Process Res. Dev. 2007, 11, 1065. (c) Shinde, G. B.; Niphade, N. C.; Deshmukh, S. P.; Toche, R. B.; Mathad, V. T. Org. Process Res. Dev. 2011, 15, 455. (84) 3-Nitrophenylboronic acid: Bannister, R. M.; Brookes, M. H.; Evans, G. R.; Katz, R. B.; Tyrrell, N. D. Org. Process Res. Dev. 2000, 4, 467. (85) Al-Zoubi, R. M.; Marion, O.; Hall, D. G. Angew. Chem., Int. Ed. 2008, 47, 2876. (86) (a) Wang, C.; Yu, H.-Z.; Fu, Y.; Guo, Q.-X. Org. Biomol. Chem. 2013, 11, 2140. (b) Marcelli, T. Angew. Chem., Int. Ed. 2010, 49, 6840. (87) Methyl esters: (a) Hartner, F. W.; Cvetovich, R. J.; Tsay, F.-R.; Amato, J. S.; Pipik, B.; Grabowski, E. J. J.; Reider, P. J. J. Org. Chem. 1999, 64, 7751. (b) Bankston, D.; Dumas, J.; Natero, R.; Riedl, B.; Monahan, M.-K.; Sibley, R. Org. Process Res. Dev. 2002, 6, 777. (c) Reichard, G. A.; Stengone, C.; Paliwal, S.; Mergelsberg, I.; Majmundar, S.; Wang, C.; Tiberi, R.; McPhail, A. T.; Piwinski, J. J.; Shih, N.-Y. Org. Lett. 2003, 5, 4249. (d) Haight, A. R.; Bailey, A. E.; Baker, W. S.; Cain, M. H.; Copp, R. R.; DeMattei, J. A.; Ford, K. L.; Henry, R. F.; Hsu, M. C.; Keyes, R. F.; King, S. A.; McLaughlin, M. A.; Melcher, L. M.; Nadler, W. R.; Oliver, P. A.; Parekh, S. I.; Patel, H. H.; Seif, L. S.; Staeger, M. A.; Wayne, G. S.; Wittenberger, S. J.; Zhang, W. Org. Process Res. Dev. 2004, 8, 897. (e) Abe, M.; Nagai, M.; Yamamoto, K.; Yamazaki, H.; Koga, I.; Satoh, Y.; Muraoka, Y.; Kurashige, S.; Ichikawa, Y.-i. Org. Process Res. Dev. 2005, 9, 570. (f) Chen, L.; Kim, Y.

M.; Kucera, D. J.; Harrison, K. E.; Bahmanyar, S.; Scott, J. M.; Yazbeck, D. J. Org. Chem. 2006, 71, 5468. (g) Mezei, T.; Mesterházy, N.; Bakó, T.; Porcs-Makkay, M.; Simig, G.; Volk, B. Org. Process Res. Dev. 2009, 13, 567. (h) Pesti, J.; Chen, C.-K.; Spangler, L.; DelMonte, A. J.; Benoit, S.; Berglund, D.; Bien, J.; Brodfuehrer, P.; Chan, Y.; Corbett, E.; Costello, C.; DeMena, P.; Discordia, R. P.; Doubleday, W.; Gao, Z.; Gingras, S.; Grosso, J.; Haas, O.; Kacsur, D.; Lai, C.; Leung, S.; Miller, M.; Muslehiddinoglu, J.; Nguyen, N.; Qiu, J.; Olzog, M.; Reiff, E.; Thoraval, D.; Totleben, M.; Vanyo, D.; Vemishetti, P.; Wasylak, J.; Wei, C. Org. Process Res. Dev. 2009, 13, 716. (i) Braish, T. F. Org. Process Res. Dev. 2009, 13, 336. (j) van der Meijden, M. W.; Leeman, M.; Gelens, E.; Noorduin, W. L.; Meekes, H.; van Enckevort, W. J. P.; Kaptein, B.; Vlieg, E.; Kellogg, R. M. Org. Process Res. Dev. 2009, 13, 1195. (k) Vartak, A. P.; Crooks, P. A. Org. Process Res. Dev. 2009, 13, 415. (l) Anelli, P. L.; Brocchetta, M.; Lattuada, L.; Manfredi, G.; Morosini, P.; Murru, M.; Palano, D.; Sipioni, M.; Visigalli, M. Org. Process Res. Dev. 2009, 13, 739. (m) Anderson, K. R.; Atkinson, S. P. L. G.; Fujiwara, T.; Giles, M. E.; Matsumoto, T.; Merifield, E.; Singleton, J. T.; Saito, T.; Sotoguchi, T.; Tornos, J. A.; Way, E. L. Org. Process Res. Dev. 2010, 14, 58. (n) Walker, M. D.; Andrews, B. I.; Burton, A. J.; Humphreys, L. D.; Kelly, G.; Schilling, M. B.; Scott, P. W. Org. Process Res. Dev. 2010, 14, 108. (o) Magnus, N. A.; Campagna, S.; Confalone, P. N.; Savage, S.; Meloni, D. J.; Waltermire, R. E.; Wethman, R. G.; Yates, M. Org. Process Res. Dev. 2010, 14, 159. (p) Zhao, Y.; Zhu, L.; Provencal, D. P.; Miller, T. A.; O’Bryan, C.; Langston, M.; Shen, M.; Bailey, D.; Sha, D.; Palmer, T.; Ho, T.; Li, M. Org. Process Res. Dev. 2012, 16, 1652. (q) Weiberth, F. J.; Yu, Y.; Subotkowski, W.; Pemberton, C. Org. Process Res. Dev. 2012, 16, 1967. (r) McLaughlin, M.; Belyk, K.; Chen, C.-y.; Linghu, X.; Pan, J.; Qian, G.; Reamer, R. A.; Xu, Y. Org. Process Res. Dev. 2013, 17, 1052. (88) Ethyl esters: (a) Wu, G.; Tormos, W. J. Org. Chem. 1997, 62, 6412. (b) Bundy, G. L.; Banitt, L. S.; Dobrowolski, P. J.; Palmer, J. R.; Schwartz, T. M.; Zimmermann, D. C.; Lipton, M. F.; Mauragis, M. A.; Veley, M. F.; Appell, R. B.; Clouse, R. C.; Daugs, E. D. Org. Process Res. Dev. 2001, 5, 144. (c) Dorow, R. L.; Herrinton, P. M.; Hohler, R. A.; Maloney, M. T.; Mauragis, M. A.; McGhee, W. E.; Moeslein, J. A.; Strohbach, J. W.; Veley, M. F. Org. Process Res. Dev. 2006, 10, 493. (d) Alimardanov, A.; Schmid, J.; Afragola, J.; Khafizova, G. Org. Process Res. Dev. 2008, 12, 424. (e) Savage, S. A.; Waltermire, R. E.; Campagna, S.; Bordawekar, S.; Dalla Riva Toma, J. Org. Process Res. Dev. 2009, 13, 510. (f) Giubellina, N.; Stabile, P.; Laval, G.; Perboni, A. D.; Cimarosti, Z.; Westerduin, P.; Cooke, J. W. B. Org. Process Res. Dev. 2010, 14, 859. (g) Huang, B.-G.; Kubiak, G.; Shay, J. J.; Pemberton, C.; Peers, J.; Hanna, R. G.; Powers, M. R.; Gamboa, J. A.; Gelormini, A. M.; Yarabe, H.; Rudisill, D. E. Org. Process Res. Dev. 2011, 15, 1040. (h) Das, P.; Srivastava, B.; Joseph, S.; Nizar, H.; Prasad, M. Org. Process Res. Dev. 2014, 18, 665. (i) Rangappa, P.; Ghosh, A.; Chitrapadi, S.; Kantikar, G.; CH, V. K.; Sythana, S.; Manjunath, S. G.; Nambiar, S.; R, S. Org. Process Res. Dev. 2014, 18, 947. (j) Patil, Y. S.; Bonde, N. L.; Kekan, A. S.; Sathe, D. G.; Das, A. Org. Process Res. Dev. 2014, 18, 1714. (k) Tian, Q.; Hoffmann, U.; Humphries, T.; Cheng, Z.; Hidber, P.; Yajima, H.; Guillemot-Plass, M.; Li, J.; Bromberger, U.; Babu, S.; Askin, D.; Gosselin, F. Org. Process Res. Dev. 2015, 19, 416. (89) tert-Butyl esters: Bellingham, R. K.; Carey, J. S.; Hussain, N.; Morgan, D. O.; Oxley, P.; Powling, L. C. Org. Process Res. Dev. 2004, 8, 279. (90) Isobutyl esters: Fleck, T. J.; McWhorter, W. W.; DeKam, R. N.; Pearlman, B. A. J. Org. Chem. 2003, 68, 9612. (91) Lactones: (a) Wu, G.; Wong, Y.; Chen, X.; Ding, Z. J. Org. Chem. 1999, 64, 3714. (b) Xu, D. D.; Waykole, L.; Calienni, J. V.; Ciszewski, L.; Lee, G. T.; Liu, W.; Szewczyk, J.; Vargas, K.; Prasad, K.; Repič, O.; Blacklock, T. J. Org. Process Res. Dev. 2003, 7, 856. (c) Li, B.; Andresen, B.; Brown, M. F.; Buzon, R. A.; Chiu, C. K. F.; Couturier, M.; Dias, E.; Urban, F. J.; Jasys, V. J.; Kath, J. C.; Kissel, W.; Le, T.; Li, Z. J.; Negri, J.; Poss, C. S.; Tucker, J.; Whritenour, D.; Zandi, K. Org. Process Res. Dev. 2005, 9, 466. (d) Abrecht, S.; Adam, J.-M.; Bromberger, U.; Diodone, R.; Fettes, A.; Fischer, R.; Goeckel, V.; Hildbrand, S.; Moine, G.; Weber, M. Org. Process Res. Dev. 2011, 15, 503. (e) Li, C.; Li, B.-F.; Chen, J.-G.; Sun, T.; Chen, Z. Org. Process 176



Review

Res. Dev. 2012, 16, 2021. (f) Michida, M.; Takayanagi, Y.; Imai, M.; Furuya, Y.; Kimura, K.; Kitawaki, T.; Tomori, H.; Kajino, H. Org. Process Res. Dev. 2013, 17, 1430. (g) Bowles, P.; Brenek, S. J.; Caron, S.; Do, N. M.; Drexler, M. T.; Duan, S.; Dubé, P.; Hansen, E. C.; Jones, B. P.; Jones, K. N.; Ljubicic, T. A.; Makowski, T. W.; Mustakis, J.; Nelson, J. D.; Olivier, M.; Peng, Z.; Perfect, H. H.; Place, D. W.; Ragan, J. A.; Salisbury, J. J.; Stanchina, C. L.; Vanderplas, B. C.; Webster, M. E.; Weekly, R. M. Org. Process Res. Dev. 2014, 18, 66. (h) von Kieseritzky, F.; Wang, Y.; Axelson, M. Org. Process Res. Dev. 2014, 18, 643. (92) Thioesters: (a) Brands, K. M. J.; Jobson, R. B.; Conrad, K. M.; Williams, J. M.; Pipik, B.; Cameron, M.; Davies, A. J.; Houghton, P. G.; Ashwood, M. S.; Cottrell, I. F.; Reamer, R. A.; Kennedy, D. J.; Dolling, U.-H.; Reider, P. J. J. Org. Chem. 2002, 67, 4771. (b) Prasada Rao, K. V. V; Dandala, R.; Sivakumaran, M. S.; Rani, A.; Naidu, A. Synth. Commun. 2007, 37, 2275. (c) Tewari, N.; Rai, B. P.; Mohammad, K.; Nizar, H.; Prasad, M. Org. Process Res. Dev. 2009, 13, 936. (93) Pentafluorophenyl esters: Zhang, H.; Schneider, S. E.; Bray, B. L.; Friedrich, P. E.; Tvermoes, N. A.; Mader, C. J.; Whight, S. R.; Niemi, T. E.; Silinski, P.; Picking, T.; Warren, M.; Wring, S. A. Org. Process Res. Dev. 2008, 12, 101. (94) NHS esters: Westermann, J.; Schneider, M.; Platzek, J.; Petrov, O. Org. Process Res. Dev. 2007, 11, 200. (95) Acetic acid: (a) van der Linden, M.; Roeters, T.; Harting, R.; Stokkingreef, E.; Gelpke, A. S.; Kemperman, G. Org. Process Res. Dev. 2008, 12, 196. (b) Sharma, P. K.; Shah, R. N.; Carver, J. P. Org. Process Res. Dev. 2008, 12, 831. (c) Chen, H.; Chen, Y.; Yuan, L.; Zou, Q. Org. Process Res. Dev. 2013, 17, 714. (96) Sulfuric acid: Marzoni, G.; Varney, M. D. Org. Process Res. Dev. 1997, 1, 81. (97) Trifluoroacetic acid: Hansen, K. B.; Hsiao, Y.; Xu, F.; Rivera, N.; Clausen, A.; Kubryk, M.; Krska, S.; Rosner, T.; Simmons, B.; Balsells, J.; Ikemoto, N.; Sun, Y.; Spindler, F.; Malan, C.; Grabowski, E. J. J.; Armstrong, J. D. J. Am. Chem. Soc. 2009, 131, 8798. (98) (a) Fyfe, M. C. T.; Gardner, L. S.; Nawano, M.; Procter, M. J.; Rasamison, C. M.; Schofield, K. L.; Shah, V. K.; Yasuda, K. (OSI Pharmaceuticals, Inc., USA; Prosidion Ltd, GB). PCT Int. Appl. 2004, WO 2004072031 A2 20040826. (b) Briner, P. H.; Fyfe, M. C. T.; Madeley, J. P.; Murray, P. J.; Procter, M. J. (Prosidion Ltd, GB); Spindler, F. (Solvias, AG). PCT Int. Appl. 2006, WO 2006016178 A1 20060216. (99) Ho, G.-J.; Mathre, D. J. J. Org. Chem. 1995, 60, 2271. (100) Weisenburger, G. A.; Vogt, P. F. Org. Process Res. Dev. 2006, 10, 1246. (101) Ueki, H.; Ellis, T. K.; Martin, C. H.; Boettiger, T. U.; Bolene, S. B.; Soloshonok, V. A. J. Org. Chem. 2003, 68, 7104. (102) Wakasugi, K.; Iida, A.; Misaki, T.; Nishii, Y.; Tanabe, Y. Adv. Synth. Catal. 2003, 345, 1209. (103) Eckert, F.; Leito, I.; Kaljurand, I.; Kutt, A.; Klamt, A.; Diedenhofen, M. J. Comput. Chem. 2009, 30, 799. (104) Um, I.; Chun, S. M.; Bae, S. K. Bull. Korean Chem. Soc. 2005, 26, 457. (105) de Koning, P. D.; Castro, N.; Gladwell, I. R.; Morrison, N. A.; Moses, I. B.; Panesar, M. S.; Pettman, A. J.; Thomson, N. M. Org. Process Res. Dev. 2011, 15, 1256. (106) http://www.acs.org/content/acs/en/greenchemistry/industrybusiness/pharmaceutical.html (accessed June 26, 2015). (107) (a) Shekhar, A. C.; Kumar, A. R.; Sathaiah, G.; Paul, V. L.; Sridhar, M.; Rao, P. S. Tetrahedron Lett. 2009, 50, 7099. (b) Wu, X.-F.; Sharif, M.; Pews-Davtyan, A.; Langer, P.; Ayub, K.; Beller, M. Eur. J. Org. Chem. 2013, 2013, 2783. (c) Hosseini-Sarvari, M.; Sharghi, H. J. Org. Chem. 2006, 71, 6652. (108) (a) Shteinberg, L. Y.; Kondratov, S. A.; Shein, S. M.; Mishchenko, S. E.; Dolmat, V. M.; Dibrova, V. M. Kinet. Catal. 1999, 40, 511. (b) Shteinberg, L. Y.; Kondratov, S. A.; Shein, S. M. Russ. J. Org. Chem. 2005, 41, 304. (c) Shteinberg, L. Y.; Kondratov, S. A.; Shein, S. M.; Marshalova, V. V. Kinet. Catal. 2007, 48, 632. (d) Shteinberg, L. Y.; Marshalova, V. V.; Dibrova, V. M.; Shein, S. M. Russ. J. Gen. Chem. 2008, 78, 1695. (e) Shteinberg, L.; Marshalova,

V. V.; Dibrova, V. M.; Shein, S. M. Russ. J. Gen. Chem. 2011, 81, 1839. (f) Hosseini-Sarvari, M.; Sodagar, E.; Doroodmand, M. M. J. Org. Chem. 2011, 76, 2853. (g) Lundberg, H.; Tinnis, F.; Adolfsson, H. Synlett 2012, 2201. (h) Deiana, C.; Sakhno, Y.; Fabbiani, M.; Pazzi, M.; Vincenti, M.; Martra, G. ChemCatChem 2013, 5, 2832. (109) (a) Talukdar, D.; Saikia, L.; Thakur, A. J. Synlett 2011, 1597. (b) Allen, C. L.; Chhatwal, A. R.; Williams, J. M. J. Chem. Commun. 2012, 48, 666. (c) Lundberg, H.; Tinnis, F.; Adolfsson, H. Chem. - Eur. J. 2012, 18, 3822. (110) Ghosh, S.; Bhaumik, A.; Mondal, J.; Mallik, A.; Sengupta, S.; Mukhopadhyay, C. Green Chem. 2012, 14, 3220. For an example of stoichiometric AlMe3 applied to the synthesis of amides, see: Li, J.; Subramaniam, K.; Smith, D.; Qiao, J. X.; Li, J. J.; Qian-Cutrone, J.; Kadow, J. F.; Vite, G. D.; Chen, B.-C. Org. Lett. 2012, 14, 214. (111) Kim, J.-G.; Jang, D. O. Synlett 2010, 1231. (112) (a) Comerford, J. W.; Clark, J. H.; Macquarrie, D. J.; Breeden, S. W. Chem. Commun. 2009, 2562. (b) Comerford, J. W.; Farmer, T. J.; Macquarrie, D. J.; Breeden, S. W.; Clark, J. H. ARKIVOC 2012, 7, 282. (113) Ali, M. A.; Siddiki, S. M. A. H.; Onodera, W.; Kon, K.; Shimizu, K.-i. ChemCatChem. 2015, 7, 3555. (114) El-Faham, A.; Funosas, R. S.; Prohens, R.; Albericio, F. Chem. Eur. J. 2009, 15, 9404. (115) Gunanathan, C.; Ben-David, Y.; Milstein, D. Science 2007, 317, 790. (116) (a) Bode, J. W.; Sohn, S. S. J. Am. Chem. Soc. 2007, 129, 13798. (b) Vora, H. U.; Rovis, T. J. Am. Chem. Soc. 2007, 129, 13796. (c) Chiang, P.-C.; Kim, Y.; Bode, J. W. Chem. Commun. 2009, 4566.

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Large-Scale Applications of Amide Coupling Reagents for the

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