Metal-Free Transamidation of Secondary Amides by NâC Cleavage

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Metal-Free Transamidation of Secondary Amides by N–C Cleavage Md. Mahbubur Rahman, Guangchen Li, and Michal Szostak J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b02013 • Publication Date (Web): 20 Aug 2019 Downloaded from pubs.acs.org on August 21, 2019

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The Journal of Organic Chemistry

Metal-Free Transamidation of Secondary Amides by N– C Cleavage Md. Mahbubur Rahman,† Guangchen Li,† and Michal Szostak*,† †

Department of Chemistry, Rutgers University, 73 Warren Street, Newark, New Jersey 07102, United States

RECEIVED DATE (to be automatically inserted after your manuscript is accepted if required according to the journal that you are submitting your paper to) Corresponding author [email protected]

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Abstract

`

Transamidation reactions represent a fundamental chemical process involving conversion of one amide functional group into another. Herein, we report a facile, highly chemoselective method for transamidation of N-Boc activated secondary amides that proceeds under exceedingly mild conditions in the absence of any additives. Because this reaction is performed in the absence of metals, oxidants or reductants, the reaction tolerates a large number of useful functionalities. The reaction is compatible with diverse amides and nucleophilic amines, affording the transamidation products in excellent yields through direct nucleophilic addition to the amide bond. The utility of this methodology is highlighted in the synthesis of Tigan, a commercial antiemetic directly from the amide bond. We expect that this new metal-free transamidation will have broad implications for the development of new transformations involving direct nucleophilic addition to the amide bond as a key step.


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1. Introduction The amide bond is one of the most important functional groups in chemistry and nature. 1–3 Because of the prevalence of amides in organic synthesis, drug discovery and polymers, new methods for the construction of amides have a major impact on the field.4 While one of the most attractive methods for the synthesis of amides involves transamidation,5 the high stability of amides resulting from nN→*C=O conjugation renders the amide N–C(O) bond very difficult to cleave.6 In particular, transamidation of secondary amides poses a formidable challenge because of the thermoneutral character of the process and the formation of undesired equilibrium mixtures.7 Recently, strategies for activation of amides by steric and electronic distortion of the N–C(O) amide bond have gained a considerable momentum (Figure 1A).8–10 This broadly applicable amide activation platform is of high interest to academic and industrial chemists because it enables to activate common amides for an array of previously elusive transformations. In this context, a number of groups have reported transamidations of sterically-distorted amides, including via metal-catalyzed and transitionmetal-free pathways.11–14 The direct activation of secondary amides by N-tert-butoxycarbonylation (NBoc) is particularly attractive15–17 because it allows one to engage common secondary amides in a diverse set of N–C(O) cleavage reactions (RE, resonance energy, RE = 7.2 kcal/mol; Winkler-Dunitz distortion,  = 29.1°; N = 8.4°; Ar = Ph, R = Ph).9 An ever-increasing drive to improve the utility, operational simplicity and environmental profile18 of reactions involving N–C cleavage11–17 in common amides led us to question whether it might be possible to increase the efficiency of transamidations of secondary amides. Herein, we report a highly chemoselective method for transamidation of N-Boc activated secondary amides that proceeds under exceedingly mild conditions in the absence of any additives (Figure 1B). The present method represents the first example of a general, metal-free method for transamidation of synthetically-useful N-Boc amides. The reactivity of N-activated twisted amides hinges upon two competing pathways: 1) nucleophilic addition, and 2) N-deprotection. The present study reports that the combination of a polar aprotic solvent and external base-free conditions significantly improves the 3 ACS Paragon Plus Environment


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reactivity in transamidation. The method relies on facile preparation of N-Boc amides directly from secondary amides, which makes the method synthetically-useful and is in sharp contrast to other activated amides. Notable features of our study include: (1) The reaction is compatible with diverse amides and nucleophilic amines, affording the transamidation products in excellent yields. (2) The method offers major advantages in terms of operational-simplicity, decreased waste generation and improved atom economy, which is important from the environmental and sustainability standpoints.18 (3) The utility of this methodology is highlighted in the synthesis of Tigan, a commercial antiemetic, directly from the amide bond.19 The strategy enabling simple secondary amides to serve broadly as electrophiles in metalfree transamidation may have broad implications for the development of new transformations involving direct nucleophilic addition to the amide bond as a key step.

Figure 1. (a) Activation of amides for N–C(O) cleavage. (b) Metal-free, highly selective transamidation of N-Boc amides (this work).


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2. Results and Discussion The site-selective N-tert-butoxycarbonylation of secondary amides proceeds in an average >80% yield, including substrates containing Lewis basic sites,9,15,16 rendering secondary amides generic electrophiles in synthetic reactions. The properties of the leaving amine, tert-butyl carbamate, make the transamidation process thermodynamically favored. We proposed that stabilization of the tetrahedral intermediate in a more polar transition state would lead to the increased efficiency of the transamidation process.20 The key consideration is the balance between the increased rate of nucleophilic addition to the N-Boc activated N–C(O) amide bond and the amide bond deprotection by N-Boc scission,9c which effectively deactivates the amide bond from mild nucleophilic addition. The synthetic utility of transamidation reactions under operationally-simple, metal-free conditions, in which the traditionally inert amide bonds are employed as electrophiles in a direct nucleophilic addition mechanism, has served as motivation for the current study. The reaction between N-Boc activated amide (1a) and morpholine was selected as a model system (Table 1). Notice that this reaction is unsuccessful under previous conditions promoted by Et3N, which leads to amide decomposition through N-deacylation pathway.14c Morpholine represents a nucleophilic amine that is deactivated by the electron-negative oxygen atom. As such, morpholine has often been used as an amine in transition-metal-catalyzed cross-coupling reactions of N-Boc amides, wherein the background reaction in the absence of transition-metal was found to be non-existent.11,12 Clearly, a strategy for the metal-free synthesis of valuable N-morpholinyl amides by transamidation of secondary amides would be of considerable utility. Morpholinyl amides function as resonance stabilized Weinreb amide equivalents in nucleophilic addition reactions via tetrahedral intermediates.9 In analogy to the classical nucleophilic addition reactions, the choice of solvent was found to have a major impact on the yield. After extensive optimization we found that the use of morpholine (2.0 equiv) in acetonitrile (1.0 M) in the absence of any other reagents led to highly efficient transamidation of amide (1a) in quantitative yield at room temperature (Table 1, entry 1). Under these conditions, several solvents could be utilized (Table 1, entries 2-10); however, acetonitrile was found to be optimal. ACS Paragon Plus Environment

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Interestingly, changes in the reaction concentration led to a reduced yield (Table 1, entries 11-13), likely as a result of slower addition and/or amide deprotection by N–Boc cleavage. Remarkably, the amount of morpholine could be reduced to 1.5 equiv and even 1.0 equiv (Table 1, entries 14-15), consistent with highly efficient transamidation. Under the optimized conditions cleavage of the alternative N–C bond was not observed. The reactions were routinely stirred for 15 h (Table 1, entries 1-15). The reaction time was not optimized; however, 30% conversion is observed after 1 h reaction time under standard conditions (Table 1, entry 1). All reactions were set up under ambient conditions in the absence of additional air, oxygen or inert gas. Further, the use of EtOH is not recommended as it leads to Ndecomposition (Table 1, entry 10).14g It is worthwhile to point out that 1) N-Ts amides cannot be easily prepared from secondary amides as, typically, these reactions require a strong base and are plagued by N-acylation; 2) N-Boc amides are significantly less reactive than N-Ts amides in metal-free transamidation (i.e., no reaction is observed with less reactive amines, including morpholine).14c Overall, this finding represents the first general method for a metal-free transamidation of synthetically useful N-Boc amides. Table 1. Optimization of the Reaction Conditionsa

entry

2a (equiv)

solvent

T (°C)

yield (%)b

1

2.0

CH3CN

25

>98

2

2.0

THF

25

84

3

2.0

toluene

25

90

4

2.0

CH2Cl2

25

94

5

2.0

Et2O

25

92

6

2.0

CHCl3

25

88

7

2.0

1,4-dioxane

25

94

8

2.0

DMF

25

83


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9

2.0

DMSO

25

82

10

2.0

EtOH

25

60

11

c

2.0

CH3CN

25

78

12d

2.0

CH3CN

25

93

13

e

2.0

CH3CN

25

97

14

1.5

CH3CN

25

>98

15

1.0

CH3CN

25

a

b

89 1

Conditions: amide (1.0 equiv), solvent (1.0 M), 25 °C, 15 h. GC/ H NMR yields. cCH3CN (0.25 M). dCH3CN (0.50 M). eCH3CN (2.0 M).

With optimized conditions in hand, the scope of this metal-free transamidation was surveyed (Schemes 1-2). As expected from the very mild, metal-free profile of this reaction, a variety of sensitive functional groups is tolerated, providing the transamidation products in high to excellent yields. As shown in Scheme1, electronic substitution of the amide at the conjugating para-position with electronneutral (3b), deactivating electron-donating (3c) and various electron-withdrawing groups (3d-3i) was well-tolerated. Particularly noteworthy is functional group tolerance to electrophilic substituents such as nitro (3e), bromo (3h) and ester (3i) that would be problematic in transition-metal-catalyzed protocols11,12 or in the reactions promoted by strong metal bases.14a,b Moreover, the reaction provides access to fluorinated amides (3f-3g) that constitute useful building blocks in pharmaceuticals.2a,b Furthermore, we were pleased to find that electron-rich five-membered heterocycles substituted at the conjugating position furnished the transamidation products in high yields (3j-3k). Notably, alkyl amides were also found to be competent electrophiles in this reaction (3l). Finally, the synthesis of ,conjugated amide (3m) demonstrates the ability of this transformation to promote transamidation of vinyl amides, albeit 60 °C is required in this case. Addition to the olefin was not observed under these conditions, attesting to the mild conditions of the present transamidation method. Furthermore, we were delighted that the scope of the amine component is also broad (Scheme 2). Primary amines with different length chains (3n-3o) as well as those containing groups sensitive in transition-metal-catalysis (3p-3q) proved to be effective in this reaction. Acyclic (3r-3t) as well as cyclic (3u-3v) secondary ACS Paragon Plus Environment

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amines afforded transamidation products in excellent yields. This includes N-Bn and N-allyl amines that would be problematic in transition-metal-catalysis,11,12 clearly showing the advantage of this mild protocol. Furthermore, -branched primary amines were tolerated (3w-3x). At present, the limit appears to be reached with bulky amines; expectedly, tert-butylamine also reacted, albeit required elevated temperature (120 °C) for transamidation (3y). It is worthwhile to point out that the method is compatible with alkyl esters, halides and electrophilic functional groups that would be problematic in other approaches.11–14 The method is not compatible with activated phenolic esters; it is well-established in the literature that activated esters are more reactive than amides.8a At the present stage of reaction development iodo and cyano substituents have not been tested. The effect of ortho-substitution on steric and electronic properties of N-activated acyclic twisted amides is currently ongoing in our laboratory. Future studies will focus on expanding the scope of transamidation and related metal-free activation methods of amide bonds.


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Scheme 1. Additive-Free Transamidation of N-Boc Amidesa,b

a

Amide (1.0 equiv), 2a (2.0 equiv), CH3CN (1.0 M), 25 °C, 15 h. bIsolated yields. c2a (1.2 equiv), 60 °C.


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Scheme 2. Additive-Free Transamidation of N-Boc Amidesa,b

a

Amide (1.0 equiv), 2a (2.0 equiv), CH3CN (1.0 M), 25 °C, 15 h. bIsolated yields. c120 °C.

Importantly, N-alkyl amides are suitable substrates (Scheme 3, 1n-1o). In this instance, nucleophilic amines react smoothly at room temperature, while the use of deactivated morpholine requires higher temperatures (120 °C), as expected from amidic resonance.9a Given thermal instability of tert-butyl carbamates, this result highlights the fast nucleophilic addition of deactivated amines in this metal-free transamidation manifold.


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Scheme 3. Additive-Free Transamidation of N-Boc/N-Alkyl Amides

To demonstrate the utility of this mild transamidation method, we accomplished the synthesis of Tigan, a commercial antiemetic for treatment of nausea directly from the amide bond (Scheme 4).19 The present synthetic route involves CDI-mediated amidation. Our method permits an alternative disconnection utilizing amide as the starting material. The reaction using equimolar quantities of the reagents (2n, 1.0 equiv) delivered Tigan in 84% yield. This reaction demonstrates the potential breadth of applications of the present method in medicinal chemistry. The synthesis of Tigan represents, to the best of our knowledge, the first example of a real-life application of any type in the burgeoning field of N–C(O) bond activation.8,11–16 This example emphasizes the potential synthetic utility of the method. Future studies will focus on the synthesis of analogues and application of N–C bond cleavage reactions in medicinal chemistry.


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Scheme 4. Synthesis of Tigan by Additive-Free Transamidation of N-Boc Amide

To gain insight into the reaction mechanism, we performed intermolecular competition experiments between differently substituted amides, which revealed electron-deficient amides to be more reactive than their electron-rich or alkyl counterparts (Scheme 5). Furthermore, intermolecular competition experiments between different amines established that the reaction is promoted by nucleophilic amines (Scheme 6). These findings provide a strong support for the acyl substitution mechanism of the amide bond,20 wherein selectivity is determined by amine nucleophilicity.21 There appears to be a scattered correlation between nucleophilicities of amines and the reactivity. Because the reactivity is also dependent on steric demand of the nucleophile, nucleophilicity provides an estimate of the reactivity in this reaction manifold. Our findings in combination with other metal-free and transition-metal-free methods permit to formulate a set of guidelines for using mild transamidation of N–Boc amides (vide infra). The NHRBoc amine can be recovered from the reaction mixture, consistent with the proposed mechanism. Guidelines for Metal-Free and Transition-Metal-Free Transamidation Reactions. The present method should be compared and contrasted with other known methods for transamidation reactions of N-activated amides.11–14 ACS Paragon Plus Environment

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(1) In principle, we recommend that metal-free transamidations described in the present study14c are used for nucleophilic amines, such as aliphatic amines and strongly nucleophilic anilines. These reactions appear to proceed through rate-limiting addition to the amide bond. (2) In contrast, transamidations with non-nucleophilic anilines are best performed using strong bases, such as LiHMDS.14a,b Mechanistically, these reactions proceed via deprotonation of the amine and are less suitable for nucleophilic aliphatic amines. (3) In cases when metal-free or transition-metal-free reactions fail to provide the desired level of efficiency, we recommend the use of Pd-12 or Ni-catalyzed11 transamidations. An important practical difference between the Pd- and Ni-catalytic systems described is the use of air-stable, well-defined Pd(II)–NHC precatalysts that make the set up robust to air and moisture.8a (4) Finally, since the present method represents the most reactive and operationally-straightforward protocol for metal-free transamidation of N-activated amides, we recommend that this reaction is tested in the first instance when developing new transamidation methods11–14 or expanding the scope of the reported methods with other amide precursors.8,9


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Scheme 5. Competition Experiments

Scheme 6. Competition Experiments


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3. Conclusions In summary, we have reported a facile method for metal-free transamidation of N-Boc activated secondary amides. Notably, the reaction proceeds under exceedingly mild conditions in the absence of any additives. This discovery provides a novel way for transamidation of the traditionally challenging secondary amides. The method offers major advantages in terms of operational-simplicity, decreased waste generation and improved atom economy, which are important factors in the search for more benign strategies in organic synthesis. The utility of this methodology has been highlighted in the synthesis of Tigan, a commercial antiemetic directly from the amide bond. In principle, a dominant aspect of amide bond activation stems from the ability to predictably form tetrahedral intermediates after selective N-activation. This advance should facilitate the development of general strategies for deploying nucleophilic addition to amide bonds. Studies to expand the reaction scope and the development of related reactions that utilize amide bond destabilization concept are underway.

Experimental Section General Methods. All starting materials reported in the manuscript have been previously described in literature or prepared by the method reported previously. All tert-butyl benzoyl(phenyl)carbamate derivatives were prepared according to standard methods.12a,14b,15a All products reported in the manuscript have been previously described, unless stated otherwise. All experiments were performed using standard Schlenk techniques under argon or nitrogen atmosphere unless stated otherwise. All solvents were purchased at the highest commercial grade and used as received or after purification by passing through activated alumina columns or distillation from sodium/benzophenone under nitrogen. All other chemicals were purchased at the highest commercial grade and used as received. 1H NMR and 13

C NMR spectra were recorded in CDCl3 on Bruker spectrometers at 500 (1H NMR) and 125 MHz (13C

NMR). HRMS were recorded using Bruker FTMS equipped with a 7.0 T magnet, and an Apollo II Dual ESI/MALDI source. For reactions that required heating, oil bath was used as the heat source (silicone ACS Paragon Plus Environment

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oil). All other general methods have been published.16b 1H NMR and

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C NMR data are given for all

compounds in the Supporting Experimental for characterization purposes. 1H NMR,

13

C NMR and

HRMS data are reported for all new compounds. All compounds have been fully characterized in accordance with the established guidelines. General Procedure for the Synthesis of Starting Materials. All amides used in this study have been prepared by established methods. 12a,14b,15a 1H NMR and 13C NMR data for all amides are given in the section below for characterization purposes. General Procedure for the Synthesis of N-Boc Amides from Secondary Amides. A previously published procedure was followed.12a An oven-dried round-bottomed flask (100 mL) containing a stir bar was charged with a secondary amide substrate (5.0 mmol, 1.0 equiv), 4-(dimethylamino)pyridine (0.5 mmol, 0.10 equiv) and dichloromethane (typically, 0.20 M). Di-tert-butyl dicarbonate (5.0 mmol, 1.0 equiv) was added in one portion and the reaction mixture was allowed to stir at room temperature for 15 h. After the indicated time, the reaction mixture was quenched with NaHCO3 (aq., sat., 10 mL), extracted with EtOAc (3× 20 mL), washed with H2O (1 x 20 mL), brine (1 x 20 mL). The organic layers were combined, dried, and concentrated under reduce pressure. Unless stated otherwise, purification by flash chromatography (EtOAc/hexanes) afforded pure products. In our hands, N-Boc activation of secondary amides typically proceeds in >80% yields. The isolated products were characterized by 1H NMR, 13C NMR, 19F NMR (if required) and HRMS (new compounds). General Procedure for Facile Transamidation Reactions. An oven-dried reaction flask containing a stir bar was charged with an amide substrate (neat, 1.0 equiv) CH3CN (typically, 1.0 M), and amine (typically, 2.0 equiv) were added with vigorous stirring at room temperature, and the reaction mixture was stirred at room temperature for an indicated time. After the indicated time, the reaction mixture was diluted with EtOAc (15 mL), washed with HCl (aq., 1.0 N, 10 mL), the aqueous layer was extracted with EtOAc (2 × 15 mL), the organic layers were combined, dried, filtered, and concentrated. A sample was analyzed by 1H NMR (CDCl3, 500 MHz) and GC-MS to obtain conversion, yield and selectivity 16 ACS Paragon Plus Environment

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using internal standard and comparison with authentic samples. The crude product was purified by chromatography (EtOAc/hexanes) to give analytically pure product. The isolated products were characterized by 1H NMR, 13C NMR, 19F NMR (if required) and HRMS (new compounds). Representative Procedure for Facile Transamidation. 1.0 Mmol Scale. An oven-dried 25 mL reaction flask containing a stir bar was charged with tert-butyl benzoyl(phenyl)carbamate (297.4 mg, 1.0 mmol, 1.0 equiv), CH3CN (1.0 mL, 1.0 M) and morpholine (174.2 mg, 2.0 mmol, 2.0 equiv), and the reaction mixture was stirred at room temperature for 15 h. After the specified time, the reaction mixture was diluted with EtOAc (30 mL), washed with HCl (aq., 1.0 N, 10 mL), the aqueous layer was extracted with EtOAc (2 × 15 mL), the organic layers were combined, dried, filtered, and concentrated. A sample was analyzed by 1H NMR (CDCl3, 500 MHz) and GC-MS to obtain conversion, yield and selectivity using internal standard and comparison with authentic samples. Purification by chromatography on silica gel (EtOAc/hexanes) afforded the title product. Yield 94% (180.1 mg). White solid. Characterization data are included in the section below. Characterization Data of Amide Starting Materials. All amides described in this manuscript were prepared directly from secondary amides by established methods. Amides 1a,12a 1b,12a 1c,12a 1d,12a 1g,12a 1i,12a 1j,12a 1l,12a 1n,12a 1o12a have been previously reported. Spectroscopic data match those reported in the literature. Amides 1e, 1f, 1h, 1k, 1m, 1p are new compounds. tert-Butyl benzoyl(phenyl)carbamate (1a). Yield 95% (1.41 g). White solid. 1H NMR (500 MHz, CDCl3) δ 7.76 (d, J = 7.1 Hz, 2H), 7.55 (t, J = 7.4 Hz, 1H), 7.49-7.43 (m, 4H), 7.37 (t, J = 7.4 Hz, 1H), 7.30 (d, J = 7.4 Hz, 2H), 1.26 (s, 9H). 13C{1H} NMR (125 MHz, CDCl3) δ 172.8, 153.3, 139.1, 137.0, 131.7, 129.2, 128.3, 128.1, 128.0, 127.8, 83.5, 27.5. tert-Butyl (4-methylbenzoyl)(phenyl)carbamate (1b). Yield 91% (1.42 g). White solid. 1H NMR (500 MHz, CDCl3) δ 7.67 (d, J = 7.9 Hz, 2H), 7.44 (t, J = 7.7 Hz, 2H), 7.35 (t, J = 7.2 Hz, 1H), 7.30-


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7.25 (m, 4H), 2.44 (s, 3H), 1.29 (s, 9H).

13C{1H}

Page 18 of 37

NMR (125 MHz, CDCl3) δ 172.7, 153.5, 142.5,

139.3, 133.9, 129.2, 128.9, 128.5, 127.9, 127.6, 83.3, 27.6, 21.6. tert-Butyl (4-methoxybenzoyl)(phenyl)carbamate (1c). Yield 87% (1.42 g). White solid. 1H NMR (500 MHz, CDCl3) δ 7.77 (d, J = 7.6 Hz, 2H), 7.43 (t, J = 7.2 Hz, 2H), 7.33 (t, J = 7.3 Hz, 1H), 7.28 (d, J = 7.9 Hz, 2H), 6.95 (d, J = 7.7 Hz, 2H), 3.88 (s, 3 H), 1.32 (s, 9H). 13C{1H} NMR (125 MHz, CDCl3) δ 172.1, 162.8, 153.5, 139.5, 130.9, 129.1, 128.7, 127.8, 127.5, 113.6, 83.1, 55.5, 27.7. tert-Butyl phenyl(4-(trifluoromethyl)benzoyl)carbamate (1d). Yield 78% (1.43 g). White solid. 1H NMR (500 MHz, CDCl3) δ 7.81 (d, J = 8.1 Hz, 2H), 7.71 (d, J = 8.1 Hz, 2H), 7.45 (t, J = 7.6 Hz, 2H), 7.37 (t, J = 7.4 Hz, 1H), 7.27 – 7.24 (m, 2H), 1.24 (s, 9H).

13C{1H}

NMR (125 MHz, CDCl3) δ 171.7,

153.2, 140.7, 138.9, 133.4 (q, JF = 32.7 Hz), 129.7, 128.5, 128.5, 128.3, 125.7 (q, JF = 3.7 Hz), 124.0 (q, JF = 273.0 Hz), 84.5, 27.8. 19F NMR (471 MHz, CDCl3) δ -62.93. tert-Butyl (4-nitrophenyl)carbamate (1e). New compound. Yield 75% (1.28 g). White solid. Mp = 102-103 °C. 1H NMR (500 MHz, CDCl3) δ 8.30 (d, J = 8.7 Hz, 2H), 7.83 (d, J = 8.8 Hz, 2H), 7.46 (t, J = 7.6 Hz, 2H), 7.39 (d, J = 7.5 Hz, 1H), 7.27 – 7.23 (m, 2H), 1.27 (s, 9H).

13C{1H}

NMR (125 MHz,

CDCl3) δ 170.9, 152.9, 149.4, 143.0, 138.5, 129.6, 128.9, 128.6, 128.3, 123.8, 84.7, 27.8. HRMS (ESITOF) calcd for C18H18N2O5Na (M+ + Na) 365.1108 found 365.1125. tert-Butyl (4-fluorobenzoyl)(phenyl)carbamate (1f). New compound. Yield 82% (1.29 g). White solid. Mp = 87-88 °C. 1H NMR (500 MHz, CDCl3) δ 7.78 – 7.72 (m, 2H), 7.42 (t, J = 7.7 Hz, 2H), 7.34 (t, J = 7.4 Hz, 1H), 7.26 – 7.22 (m, 2H), 7.14 – 7.10 (m, 2H), 1.28 (s, 9H).

13C{1H}

NMR (125

MHz, CDCl3) δ 171.8, 165.1 (d, JF = 253.5 Hz), 153.5, 139.3, 133.2 (d, JF = 3.2 Hz), 131.0 (d, JF = 9.0 Hz), 129.5, 128.1 (d, JF = 4.9 Hz), 115.8, 115.6, 83.9, 27.8.

19F

NMR (471 MHz, CDCl3) δ -106.89.

HRMS (ESI-TOF) calcd for C36H36F2N2O6Na (2M+ + Na) 653.2434 found 653.2435. tert-Butyl phenyl(3,4-difluorobenzoyl)carbamate (1g). Yield 80% (1.33 g). White solid. 1H NMR (500 MHz, CDCl3) δ 7.56 (t, J = 8.8 Hz, 1H), 7.53 – 7.47 (m, 1H), 7.43 (t, J = 7.6 Hz, 2H), 7.35 (t, J = ACS Paragon Plus Environment

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7.4 Hz, 1H), 7.27 – 7.19 (m, 3H), 1.31 (s, 9H).

13C{1H}

NMR (125 MHz, CDCl3) δ 170.7, 153.9 (dd,

JF = 255.65 Hz, JF = 12.6 Hz), 153.4, 150.4 (dd, JF = 150.9 Hz, JF = 13.1 Hz), 139.1, 133.9 (dd, JF = 5.1 Hz, JF = 4.0 Hz), 129.6, 128.4, 128.2, 125.3 (dd, JF = 7.1, JF = 3.7 Hz), 118.2 (d, JF = 19.2 Hz), 117.6 (d, JF = 18.0 Hz), 84.3, 27.9. 19F NMR (471 MHz, CDCl3) δ - 131.63, -136.54. tert-Butyl (4-bromobenzoyl)(phenyl)carbamate (1h). New compound. Yield 83% (1.57 g). White solid. Mp = 85-86 °C. 1H NMR (500 MHz, CDCl3) δ 7.63 – 7.54 (m, 4H), 7.42 (t, J = 7.6 Hz, 2H), 7.35 (t, J = 7.4 Hz, 1H), 7.23 (d, J = 7.5 Hz, 2H), 1.28 (s, 9H).

13C{1H}

NMR (125 MHz, CDCl3) δ

171.9, 153.3, 139.1, 135.9, 131.8, 130.0, 129.5, 128.2, 128.2, 126.6, 84.1, 27.8. HRMS (ESI-TOF) calcd for C18H18BrNO3K (M+ + K) 414.0102 found 414.0118. tert-Butyl phenyl((4-(methoxycarbonyl)benzoyl)carbamate (1i). Yield 71% (1.26 g). White solid. 1H

NMR (500 MHz, CDCl3) δ 8.14 (d, J = 8.1 Hz, 2H), 7.78 (d, J = 8.1 Hz, 2H), 7.46 (t, J = 7.6 Hz,

2H), 7.38 (t, J = 7.3 Hz, 1H), 7.28 (d, J = 7.8 Hz, 2H), 3.97 (s, 3H), 1.26 (s, 9H). 13C{1H} NMR (125 MHz, CDCl3) δ 171.8, 166.2, 152.9, 141.0, 138.6, 132.5, 129.5, 129.3, 128.1, 128.0, 127.8, 84.0, 52.4, 27.5. tert-Butyl (furan-2-carbonyl)(phenyl)carbamate (1j). Yield 81% (1.17 g). White solid. 1H NMR (500 MHz, CDCl3) δ 7.57-7.54 (m, 1H), 7.43 (t, J = 7.6 Hz, 2H), 7.35 (t, J = 7.4 Hz, 1H), 7.28 (d, J = 7.2 Hz, 2H), 7.04 (d, J = 3.5 Hz, 1H), 6.53 (dd, J = 3.5, 1.7 Hz, 1H), 1.42 (s, 9H). 13C{1H} NMR (125 MHz, CDCl3) δ 161.2, 152.8, 148.5, 145.1, 138.6, 129.2, 128.0, 127.9, 118.1, 112.3, 83.3, 27.7. tert-Butyl phenyl(thiophene-2-carbonyl)carbamate (1k). New compound. Yield 85% (1.29 g). White solid. Mp = 86-87 °C. 1H NMR (500 MHz, CDCl3) δ 7.56 (dd, J = 4.9, 1.0 Hz, 1H), 7.48 (dd, J = 3.8, 1.0 Hz, 1H), 7.40 (t, J = 7.6 Hz, 2H), 7.33 (t, J = 7.4 Hz, 1H), 7.28 – 7.26 (m, 2H), 7.03 (dd, J = 4.9, 3.9 Hz, 1H), 1.41 (s, 9H).

13C{1H}

NMR (125 MHz, CDCl3) δ 165.3, 153.4, 139.4, 139.4, 133.4,

133.0, 129.4, 128.1, 128.1, 127.6, 83.6, 28.0. HRMS (ESI-TOF) calcd for C16H17NO3SNa (M+ + Na) 326.0821 found 326.0838. ACS Paragon Plus Environment

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tert-Butyl (1-decanoyl)(phenyl)carbamate (1l). Yield 88% (1.53 g). White solid. 1H NMR (500 MHz, CDCl3) δ 7.41 (t, J = 7.2 Hz, 2H), 7.34 (t, J = 7.3 Hz, 1H), 7.09 (d, J = 7.7 Hz, 2H), 2.92 (t, J = 7.4 Hz, 2H), 1.70 (p, J = 7.3, 6.8 Hz, 2H), 1.40 (s, 9H), 1.29 (s, 12H), 0.90 (t, J = 6.4 Hz, 3H). 13C{1H} NMR (125 MHz, CDCl3) δ 176.0, 152.8, 139.2, 128.9, 128.2, 127.7, 82.9, 38.0, 31.9, 29.5, 29.3, 29.2, 27.8, 25.0, 22.7, 14.1. tert-Butyl cinnamoyl(phenyl)carbamate (1m). New compound. Yield 72% (1.16 g). White solid. Mp = 117-118 °C. 1H NMR (500 MHz, CDCl3) δ 7.76 (d, J = 15.6 Hz, 1H), 7.57 – 7.54 (m, 2H), 7.44 – 7.34 (m, 7H), 7.17 (d, J = 7.4 Hz, 2H), 1.43 (s, 9H).

13C{1H}

NMR (125 MHz, CDCl3) δ 168.5,

153.2, 144.6, 139.4, 135.3, 130.4, 129.3, 129.1, 128.6, 128.6, 128.1, 121.0, 83.6, 28.2. HRMS (ESITOF) calcd for C40H42N2O6Na (2M+ + Na) 669.2935 found 669.2946. tert-Butyl benzoyl(methyl)carbamate (1n). Yield 85% (1.01 g). Colorless oil. 1H NMR (500 MHz, CDCl3) δ 7.53 (d, J = 7.2 Hz, 2H), 7.48 (t, J = 7.4 Hz, 1H), 7.40 (t, J = 7.5 Hz, 2H), 3.33 (s, 3 H), 1.17 (s, 9H). 13C{1H} NMR (125 MHz, CDCl3) δ 173.6, 153.5, 137.9, 130.9, 128.0, 127.4, 83.0, 32.6, 27.4. tert-Butyl benzoyl(benzyl)carbamate (1o). Yield 91% (1.42 g). White solid. 1H NMR (500 MHz, CDCl3) δ 7.54 (d, J = 7.0 Hz, 2H), 7.47 (dd, J = 10.9, 7.4 Hz, 3H), 7.41 (d, J = 7.7 Hz, 2H), 7.37 (s, 2H), 7.30 (s, 1H), 5.02 (s, 2H), 1.15 (s, 9H). 13C{1H} NMR (125 MHz, CDCl3) δ 173.1, 153.5, 137.9, 137.7, 131.0, 128.5, 128.2, 128.1, 127.5, 127.4, 83.2, 48.9, 27.4. tert-Butyl phenyl(3,4,5-trimethoxybenzoyl)carbamate (1p). New compound. Yield 74% (1.43 g). White solid. Mp = 95-96 °C. 1H NMR (500 MHz, CDCl3) δ 7.43 – 7.39 (m, 2H), 7.34 – 7.30 (m, 1H), 7.25 – 7.21 (m, 2H), 6.98 (s, 2H), 3.89 (s, 3H), 3.86 (s, 6H), 1.31 (s, 9H).

13C{1H}

NMR (125 MHz,

CDCl3) δ 172.4, 153.8, 153.3, 141.8, 139.6, 131.8, 129.5, 127.9, 127.9, 106.3, 83.7, 61.3, 56.6, 27.9. HRMS (ESI-TOF) calcd for C42H50N2O12Na (2M+ + Na) 797.3256 found 797.3281. Characterization Data of Transamidation Products. Amides 3a,22 3b,22 3c,22 3d,24 3e,24 3f,23 3h,24 3i,25 3j,24 3k,24 3l,26 3m,27 3n,11c 3o,11c 3p,11c 3q,28 3r,11c 3s,11c 3t,28 3u,28 3v,28 3w,11c 3x,29 3y,28 430 have ACS Paragon Plus Environment

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been previously reported. Spectroscopic data match those reported in the literature. Amide 3g is a new compound. Morpholino(phenyl)methanone (3a). According to the general procedure, the reaction of tert-butyl benzoyl(phenyl)carbamate (59.5 mg, 0.20 mmol, 1.0 equiv) with morpholine (34.8 mg, 0.40 mmol, 2.0 equiv) in CH3CN (1.0 M) at room temperature for 15 h, afforded after work-up and chromatography the title compound in 92% yield (35.2 mg). White solid. 1H NMR (500 MHz, CDCl3) δ 7.45 – 7.35 (m, 5H), 3.76 (m, 4H), 3.64 (m, 2H), 3.45 (m, 2H).

13C{1H}

NMR (125 MHz, CDCl3) δ 170.6, 135.6,

130.1, 128.7, 127.3, 67.2, 48.4, 42.7. Morpholino(p-tolyl)methanone (3b). According to the general procedure, the reaction of tert-butyl (4-methylbenzoyl)(phenyl)carbamate (62.3 mg, 0.20 mmol, 1.0 equiv) with morpholine (34.8 mg, 0.40 mmol, 2.0 equiv) in CH3CN (1.0 M) at room temperature for 15 h, afforded after work-up and chromatography the title compound in 89% yield (36.5 mg). White solid. 1H NMR (500 MHz, CDCl3) δ 7.31 (d, J = 8.0 Hz, 2H), 7.21 (d, J = 7.9 Hz, 2H), 3.69 – 3.49 (m, 8H), 2.38 (s, 3H). 13C{1H} NMR (125 MHz, CDCl3) δ 170.9, 140.4, 132.7, 129.4, 127.5, 67.2, 48.7, 42.9, 21.7. (4-Methoxyphenyl)(morpholino)methanone (3c). According to the general procedure, the reaction of tert-butyl (4-methoxybenzoyl)(phenyl)carbamate (65.5 mg, 0.20 mmol, 1.0 equiv) with morpholine (34.8 mg, 0.40 mmol, 2.0 equiv) in CH3CN (1.0 M) at room temperature for 15 h, afforded after workup and chromatography the title compound in 90% yield (39.8 mg). White solid. 1H NMR (500 MHz, CDCl3) δ 7.41 – 7.35 (m, 2H), 6.94 – 6.89 (m, 2H), 3.83 (s, 3H), 3.69 – 3.63 (m, 8H). 13C{1H} NMR (125 MHz, CDCl3) δ 170.7, 161.2, 129.5, 127.6, 114.1, 67.2, 55.6, 48.1, 44.1. Morpholino(4-(trifluoromethyl)phenyl)methanone (3d). According to the general procedure, the reaction of tert-butyl phenyl(4-(trifluoromethyl)benzoyl)carbamate (73.1 mg, 0.20 mmol) with morpholine (34.8 mg, 0.40 mmol, 2.0 equiv) in CH3CN (1.0 M) at room temperature for 15 h, afforded after work-up and chromatography the title compound in 88% yield (45.6 mg). White solid. 1H NMR ACS Paragon Plus Environment

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Page 22 of 37

(500 MHz, CDCl3) δ 7.69 (d, J = 8.2 Hz, 2H), 7.52 (d, J = 8.2 Hz, 2H), 3.79 (m, 4H), 3.62 (m, 2H), 3.40 (m, 2H). 13C{1H} NMR (125 MHz, CDCl3) δ 169.3, 139.2, 132.2 (q, JF = 32.76 Hz), 127.8, 126.0 (q, JF = 3.74 Hz), 124.0 (q, JF = 272.91 Hz), 67.1, 48.4, 42.9. 19F NMR (471 MHz, CDCl3) δ -62.94. Morpholino(4-nitrophenyl)methanone (3e). According to the general procedure, the reaction of tertbutyl (4-nitro-phenyl)carbamate (68.5 mg, 0.20 mmol, 1.0 equiv) with morpholine (34.8 mg, 0.40 mmol, 2.0 equiv) in CH3CN (1.0 M) at room temperature for 15 h, afforded after work-up and chromatography the title compound in 87% yield (41.1 mg). Yellow solid. 1H NMR (500 MHz, CDCl3) δ 8.32 – 8.25 (m, 2H), 7.61 – 7.54 (m, 2H), 3.80 (m, 4H), 3.63 (m, 2H), 3.38 (m, 2H). 13C{1H} NMR (125 MHz, CDCl3) δ 168.4, 148.8, 141.8, 128.5, 124.3, 67.1, 48.4, 42.9. (4-Fluorophenyl)(morpholino)methanone (3f). According to the general procedure, the reaction of tert-butyl (4-fluorobenzoyl)(phenyl)carbamate (63.1 mg, 0.20 mmol, 1.0 equiv) with morpholine (34.8 mg, 0.40 mmol, 2.0 equiv) in CH3CN (1.0 M) at room temperature for 15 h, afforded after work-up and chromatography the title compound in 89% yield (37.6 mg). Colorless oil. 1H NMR (500 MHz, CDCl3) δ 7.45 – 7.38 (m, 2H), 7.13 – 7.06 (m, 2H), 3.69 – 3.48 (m, 8H). 13C{1H} NMR (125 MHz, CDCl3) δ 169.8, 163.8 (d, JF = 250.8 Hz), 131.6 (d, JF = 3.5 Hz), 129.7 (d, JF = 8.5 Hz), 116.0 (d, JF = 21.9 Hz), 67.1, 48.6, 43.0. 19F NMR (471 MHz, CDCl3) δ -109.91. (3,4-Difluorophenyl)(morpholino)methanone (3g). According to the general procedure, the reaction of tert-butyl phenyl(3,4-difluorobenzoyl)carbamate (66.7 mg, 0.20 mmol, 1.0 equiv) with morpholine (34.8 mg, 0.40 mmol, 2.0 equiv) in CH3CN (1.0 M) at room temperature for 15 h, afforded after workup and chromatography the title compound in 81% yield (36.8 mg). New compound. Colorless oil. 1H NMR (500 MHz, CDCl3) δ 7.29 – 7.24 (m, 1H), 7.24 – 7.18 (m, 1H), 7.18 – 7.13 (m, 1H), 3.69 – 3.49 (m, 8H).

13C{1H}

NMR (125 MHz, CDCl3) δ 168.4, 151.6 (dd, JF = 253.0 Hz, JF = 12.6 Hz), 150.5

(dd, JF = 251.5 Hz, JF = 12.9 Hz), 132.4 (t, JF = 4.7 Hz), 124.1 (dd, JF = 6.8 Hz, JF = 4.0 Hz), 118.0 (d, JF = 17.7 Hz), 117.3 (d, JF = 18.1 Hz), 67.1, 48.4, 43.1.

19F

NMR (471 MHz, CDCl3) δ -134.56, -

136.00. HRMS (ESI-TOF) calcd for C11H11F2NO2Na (M+ + Na) 250.0650 found 250.0634. ACS Paragon Plus Environment

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(4-Bromophenyl)(morpholino)methanone (3h). According to the general procedure, the reaction of tert-butyl (4-bromobenzoyl)(phenyl)carbamate (75.2 mg, 0.20 mmol, 1.0 equiv) with morpholine (34.8 mg, 0.40 mmol, 2.0 equiv) in CH3CN (1.0 M) at room temperature for 15 h, afforded after work-up and chromatography the title compound in 85% yield (45.9 mg). White solid. 1H NMR (500 MHz, CDCl3) δ 7.55 (d, J = 8.1 Hz, 2H), 7.29 (d, J = 8.2 Hz, 2H), 3.74 (m, 6H), 3.43 (m, 2H).

13C{1H}

NMR (125

MHz, CDCl3) δ 169.7, 134.4, 132.1, 129.2, 124.6, 67.1, 48.6, 43.0. Methyl 4-(morpholine-4-carbonyl)benzoate (3i). According to the general procedure, the reaction of tert-butyl benzoyl(phenyl)carbamate (71.1 mg, 0.20 mmol, 1.0 equiv) with morpholine (34.8 mg, 0.40 mmol, 2.0 equiv) in CH3CN (1.0 M) at room temperature for 15 h, afforded after work-up and chromatography the title compound in 85% yield (42.4 mg). Yellow solid. 1H NMR (500 MHz, CDCl3) δ 8.09 (d, J = 8.2 Hz, 2H), 7.47 (d, J = 8.2 Hz, 2H), 3.93 (s, 3H), 3.78 (m, 4H), 3.62 (m, 2H), 3.39 (m, 2H).

13C{1H}

NMR (125 MHz, CDCl3) δ 169.7, 166.6, 139.9, 131.7, 130.2, 127.4, 67.2, 52.7, 48.4,

42.9. Furan-2-yl(morpholino)methanone (3j). According to the general procedure, the reaction of tertButyl (furan-2-carbonyl)(phenyl)carbamate (57.5 mg, 0.20 mmol, 1.0 equiv) with morpholine (34.8 mg, 0.40 mmol, 2.0 equiv) in CH3CN (1.0 M) at room temperature for 15 h, afforded after work-up and chromatography the title compound in 85% yield (30.8 mg). White solid. 1H NMR (500 MHz, CDCl3) δ 7.48 (dd, J = 1.6, 0.7 Hz, 1H), 7.03 (dd, J = 3.5, 0.6 Hz, 1H), 6.48 (dd, J = 3.5, 1.8 Hz, 1H), 3.82 (brs, 4H), 3.76 – 3.72 (m, 4H).

13C{1H}

NMR (125 MHz, CDCl3) δ 159.5, 148.162 144.1, 117.1, 111.7,

67.3. Morpholino(thiophen-2-yl)methanone (3k). According to the general procedure, the reaction of tert-butyl benzoyl(phenyl)carbamate (60.6 mg, 0.20 mmol, 1.0 equiv) with morpholine (34.8 mg, 0.40 mmol, 2.0 equiv) in CH3CN (1.0 M) at room temperature for 15 h, afforded after work-up and chromatography the title compound in 80% yield (31.5 mg). Yellow solid. 1H NMR (500 MHz, CDCl3) δ 7.46 (dd, J = 5.0, 0.9 Hz, 1H), 7.29 (dd, J = 3.6, 0.9 Hz, 1H), 7.05 (dd, J = 5.0, 3.7 Hz, 1H), 3.78 – 23 ACS Paragon Plus Environment


3.75 (m, 4H), 3.74 – 3.71 (m, 4H).

13C{1H}

Page 24 of 37

NMR (125 MHz, CDCl3) δ 163.9, 136.9, 129.2, 129.1,

127.0, 67.1, 45.9. 1-Morpholinodecan-1-one (3l). According to the general procedure, the reaction of tert-butyl (1decanoyl)(phenyl)carbamate (69.5 mg, 0.20 mmol, 1.0 equiv) with morpholine (34.8 mg, 0.40 mmol, 2.0 equiv) in CH3CN (1.0 M) at room temperature for 15 h, afforded after work-up and chromatography the title compound in 80% yield (24.1 mg). Colorless oil. 1H NMR (500 MHz, CDCl3) δ 3.69 – 3.63 (m, 4H), 3.60 – 3.62 (m, 2H), 3.49 – 3.42 (m, 2H), 2.33 – 2.26 (m, 2H), 1.65 – 1.58 (m, 2H), 1.34 – 1.23 (m, 12H), 0.87 (t, J = 6.7 Hz, 3H). 13C{1H} NMR (125 MHz, CDCl3) δ 172.2, 67.3, 67.1, 46.4, 42.2, 33.5, 32.2, 29.8, 29.8, 29.8, 29.6, 25.6, 23.0, 14.4. (E)-1-Morpholino-3-phenylprop-2-en-1-one (3m). According to the general procedure, the reaction of tert-butyl cinnamoyl(phenyl)carbamate (64.7 mg, 0.20 mmol, 1.0 equiv) with morpholine (20.9 mg, 0.24 mmol, 1.2 equiv) in CH3CN (1.0 M) at 60 °C for 15 h, afforded after work-up and chromatography the title compound (3l) in 66% yield (28.7 mg). White solid. 1H NMR (500 MHz, CDCl3) δ 7.70 (d, J = 15.4 Hz, 1H), 7.54 – 7.49 (m, 2H), 7.40 – 7.33 (m, 3H), 6.84 (d, J = 15.4 Hz, 1H), 3.73 (m, 6H), 3.67 (m, 2H).

13C{1H}

NMR (125 MHz, CDCl3) δ 165.9, 143.5, 135.5, 130.1, 129.2, 128.1, 116.9, 67.2,

46.6, 42.8. N-Butylbenzamide (3n). According to the general procedure, the reaction of tert-butyl benzoyl(phenyl)carbamate (59.5 mg, 0.20 mmol, 1.0 equiv) with n-butylamine (29.3 mg, 0.40 mmol, 2.0 equiv) in CH3CN (1.0 M) at room temperature for 15 h, afforded after work-up and chromatography the title compound in 92% yield (32.6 mg). Colorless oil. 1H NMR (500 MHz, CDCl3) δ 7.78 – 7.73 (m, 2H), 7.48 (t, J = 7.3 Hz, 1H), 7.42 (t, J = 7.7 Hz, 2H), 6.17 (s, 1H), 3.45 (q, J = 6.6 Hz, 2H), 1.63 – 1.56 (m, 2H), 1.45 – 1.37 (m, 2H), 0.96 (t, J = 7.4 Hz, 3H). 13C{1H} NMR (125 MHz, CDCl3) δ 167.8, 135.2, 131.6, 128.9, 127.2, 40.1, 32.1, 20.5, 14.1.


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N-Dodecylbenzamide (3o). According to the general procedure, the reaction of tert-butyl benzoyl(phenyl)carbamate (59.5 mg, 0.20 mmol, 1.0 equiv) with n-decylamine (74.1 mg, 0.40 mmol, 2.0 equiv) in CH3CN (1.0 M) at room temperature for 15 h, afforded after work-up and chromatography the title compound in 91% yield (52.7 mg). White solid. 1H NMR (500 MHz, CDCl3) δ 7.76 – 7.74 (m, 2H), 7.53 – 7.46 (m, 1H), 7.46 – 7.39 (m, 2H), 6.10 (s, 1H), 3.45 (q, J = 6.7 Hz, 2H), 1.65 – 1.58 (m, 2H), 1.41 – 1.24 (m, 18H), 0.88 (t, J = 7.0 Hz, 3H). 13C{1H} NMR (125 MHz, CDCl3) δ 167.8, 135.3, 131.6, 128.9, 127.2, 40.5, 32.3, 30.1, 30.0, 30.0, 29.9, 29.9, 29.7, 27.4, 23.0, 14.5. N-Benzylbenzamide (3p). According to the general procedure, the reaction of tert-butyl benzoyl(phenyl)carbamate (59.5 mg, 0.20 mmol, 1.0 equiv) with benzylamine (42.9 mg, 0.40 mmol, 2.0 equiv) in CH3CN (1.0 M) at room temperature for 15 h, afforded after work-up and chromatography the title compound in 91% yield (38.4 mg). White solid. 1H NMR (500 MHz, CDCl3) δ 7.80 – 7.78 (m, 2H), 7.53 – 7.47 (m, 1H), 7.46 – 7.40 (m, 2H), 7.39 – 7.32 (m, 4H), 7.30 (m, 1H), 6.43 (s, 1H), 4.65 (d, J = 5.7 Hz, 2H). 13C{1H} NMR (125 MHz, CDCl3) δ 167.7, 138.5, 134.8, 131.9, 129.2, 129.0, 128.3, 128.0, 127.3, 44.5. N-Allylbenzamide (3q). According to the general procedure, the reaction of tert-butyl benzoyl(phenyl)carbamate (59.5 mg, 0.20 mmol, 1.0 equiv) with allylamine (22.8 mg, 0.40 mmol, 2.0 equiv) in CH3CN (1.0 M) at room temperature for 15 h, afforded after work-up and chromatography the title compound in 92% yield (29.7 mg). Colorless oil. 1H NMR (500 MHz, CDCl3) δ 7.79 – 7.77 (dd, J = 5.2, 3.3 Hz, 2H), 7.53 – 7.48 (m, 1H), 7.46 – 7.41 (m, 2H), 6.19 (s, 1H), 5.99 – 5.90 (m, 1H), 5.30 – 5.25 (m, 1H), 5.21 – 5.17 (m, 1H), 4.10 (tt, J = 5.7, 1.5 Hz, 2H). 13C{1H} NMR (125 MHz, CDCl3) δ 167.6, 134.9, 134.5, 131.9, 129.0, 127.2, 117.1, 42.8. N,N-Diethylbenzamide (3r). According to the general procedure, the reaction of tert-butyl benzoyl(phenyl)carbamate (59.5 mg, 0.20 mmol, 1.0 equiv) with diethylamine (29.3 mg, 0.40 mmol, 2.0 equiv) in CH3CN (1.0 M) at room temperature for 15 h, afforded after work-up and chromatography the title compound in 78% yield (27.6 mg). White solid. 1H NMR (500 MHz, CDCl3) δ 7.41 – 7.33 (m, 25 ACS Paragon Plus Environment


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5H), 3.55 (s, 2H), 3.25 (s, 2H), 1.25 (s, 3H), 1.11 (s, 3H). 13C{1H} NMR (125 MHz, CDCl3) δ 171.5, 137.5, 129.3, 128.6, 126.5, 43.5, 39.5, 14.4, 13.1. N-Benzyl-N-methylbenzamide (3s). According to the general procedure, the reaction of tert-butyl benzoyl(phenyl)carbamate (59.5 mg, 0.20 mmol, 1.0 equiv) with N-benzylmethylamine (48.5 mg, 0.40 mmol, 2.0 equiv) in CH3CN (1.0 M) at room temperature for 15 h, afforded after work-up and chromatography the title compound in 80% yield (36.0 mg). Colorless oil. 1H NMR (500 MHz, CDCl3) δ 7.47 – 7.45 (m, 2H), 7.40 (brs, 2H), 7.36 (brs, 4H), 7.32 – 7.28 (m, 1H), 7.18 (brs, 1H), 4.77 (s, 1H), 4.52 (s, 1H), 3.03 (s, 1H), 2.86 (s, 2H). 13C{1H} NMR (125 MHz, CDCl3) δ 173.6, 171.9, 137.6, 136.9, 136.5, 129.9, 129.1, 129.0, 128.7, 128.5, 127.8, 127.3, 127.2, 55.5, 51.2, 37.3, 33.5. N,N-Diallylbenzamide (3t). According to the general procedure, the reaction of tert-butyl benzoyl(phenyl)carbamate (59.5 mg, 0.20 mmol, 1.0 equiv) with diallylamine (38.9 mg, 0.40 mmol, 2.0 equiv) in CH3CN (1.0 M) at room temperature for 15 h, afforded after work-up and chromatography the title compound in 81% yield (32.6 mg). Colorless oil. 1H NMR (500 MHz, CDCl3) δ 7.44 – 7.42 (m, 2H), 7.41 – 7.36 (m, 3H), 5.88 (s, 1H), 5.73 (s, 1H), 5.24 (q, J = 1.5 Hz, 1H), 5.22 (q, J = 1.25 Hz, 1H), 5.21 (s, 1H), 5.18 (s, 1H), 4.14 (s, 2H), 3.83 (s, 2H). 13C{1H} NMR (125 MHz, CDCl3) δ 172.0, 136.6, 133.5, 133.1, 129.9, 128.6, 126.9, 117.9, 51.0, 47.2. Phenyl(pyrrolidin-1-yl)methanone (3u). According to the general procedure, the reaction of tertbutyl benzoyl(phenyl)carbamate (59.5 mg, 0.20 mmol, 1.0 equiv) with pyrrolidine (28.5 mg, 0.40 mmol, 2.0 equiv) in CH3CN (1.0 M) at room temperature for 15 h, afforded after work-up and chromatography the title compound in 92% yield (32.2 mg). Colorless oil. 1H NMR (500 MHz, CDCl3) δ 7.52 – 7.49 (m, 2H), 7.41 – 7.36 (m, 3H), 3.65 (t, J = 7.0 Hz, 2H), 3.42 (t, J = 6.6 Hz, 2H), 1.99 – 1.93 (m, 2H), 1.90 – 1.84 (m, 2H). 13C{1H} NMR (125 MHz, CDCl3) δ 170.1, 137.6, 130.1, 128.6, 127.4, 49.9, 46.5, 26.7, 24.8.


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Phenyl(piperidin-1-yl)methanone (3v). According to the general procedure, the reaction of tertbutyl benzoyl(phenyl)carbamate (59.5 mg, 0.20 mmol, 1.0 equiv) with piperidine (34.1 mg, 0.40 mmol, 2.0 equiv) in CH3CN (1.0 M) at room temperature for 15 h, afforded after work-up and chromatography the title compound in 88% yield (33.3 mg). Colorless oil. 1H NMR (500 MHz, CDCl3) δ 7.39 (m, 5H), 3.71 (s, 2H), 3.34 (s, 2H), 1.68 (s, 4H), 1.51 (s, 2H). 13C{1H} NMR (125 MHz, CDCl3) δ 170.5, 136.7, 129.5, 128.6, 127.0, 48.9, 43.3, 26.7, 25.8, 24.8. N-Isopropylbenzamide (3w). According to the general procedure, the reaction of tert-butyl benzoyl(phenyl)carbamate (59.5 mg, 0.20 mmol, 1.0 equiv) with iso-propylamine (23.6 mg, 0.40 mmol, 2.0 equiv) in CH3CN (1.0 M) at room temperature for 15 h, afforded after work-up and chromatography the title compound in 87% yield (28.4 mg). White solid. 1H NMR (500 MHz, CDCl3) δ 7.75 – 7.73 (m, 2H), 7.50 – 7.44 (m, 1H), 7.43 – 7.38 (m, 2H), 6.00 (s, 1H), 4.33 – 4.23 (m, 1H), 1.26 (d, J = 6.6 Hz, 6H). 13C{1H} NMR (125 MHz, CDCl3) δ 167.0, 135.3, 131.6, 128.8, 127.1, 42.2, 23.2. N-Cyclohexylbenzamide (3x). According to the general procedure, the reaction of tert-butyl benzoyl(phenyl)carbamate (59.5 mg, 0.20 mmol, 1.0 equiv) with cyclohexylamine (39.7 mg, 0.40 mmol, 2.0 equiv) in CH3CN (1.0 M) at room temperature for 15 h, afforded after work-up and chromatography the title compound in 90% yield (36.6 mg). White solid. 1H NMR (500 MHz, CDCl3) δ 7.77 – 7.72 (m, 2H), 7.50 – 7.45 (m, 1H), 7.44 – 7.39 (m, 2H), 6.00 (s, 1H), 4.01 – 3.94 (m, 1H), 2.06 – 1.99 (m, 2H), 1.79 – 1.71 (m, 2H), 1.68 – 1.62 (m, 1H), 1.47 – 1.38 (m, 2H), 1.28 – 1.15 (m, 3H). 13C{1H}

NMR (125 MHz, CDCl3) δ 166.9, 135.4, 131.5, 128.8, 127.2, 49.0, 33.5, 25.9, 25.2.

N-(tert-Butyl)benzamide (3y). According to the general procedure, the reaction of tert-butyl benzoyl(phenyl)carbamate (59.5 mg, 0.20 mmol, 1.0 equiv) with tert-butylamine (29.3 mg, 0.40 mmol, 2.0 equiv) in CH3CN (1.0 M) at 120 °C for 15 h, afforded after work-up and chromatography the title compound in 81% yield (28.7 mg). White solid. 1H NMR (500 MHz, CDCl3) δ 7.74 – 7.69 (m, 2H), 7.49 – 7.44 (m, 1H), 7.43 – 7.39 (m, 2H), 5.93 (s, 1H), 1.47 (s, 9H). 13C{1H} NMR (125 MHz, CDCl3) δ 167.2, 136.3, 131.4, 128.8, 127.0, 51.9, 29.2. ACS Paragon Plus Environment

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N-Butylbenzamide (3n), Transamidation of Amide (1n) with n-Butylamine. According to the general procedure, the reaction of tert-butyl benzoyl(methyl)carbamate (47.0 mg, 0.20 mmol, 1.0 equiv) with n-butylamine (29.3 mg, 0.40 mmol, 2.0 equiv) in CH3CN (1.0 M) at room temperature for 15 h, afforded after work-up and chromatography the title compound in 89% yield (31.5 mg). Colorless oil. 1H

NMR (500 MHz, CDCl3) δ 7.78 – 7.73 (m, 2H), 7.48 (t, J = 7.3 Hz, 1H), 7.42 (t, J = 7.7 Hz, 2H),

6.17 (s, 1H), 3.45 (q, J = 6.6 Hz, 2H), 1.63 – 1.56 (m, 2H), 1.45 – 1.37 (m, 2H), 0.96 (t, J = 7.4 Hz, 3H). 13C{1H}

NMR (125 MHz, CDCl3) δ 167.8, 135.2, 131.6, 128.9, 127.2, 40.1, 32.1, 20.5, 14.1.

Morpholino(phenyl)methanone (3a), Transamidation of Amide (1n) with Morpholine. According to the general procedure, the reaction of tert-butyl benzoyl(methyl)carbamate (47.0 mg, 0.20 mmol, 1.0 equiv) with morpholine (34.8 mg, 0.40 mmol, 2.0 equiv) in CH3CN (1.0 M) at 120 °C for 15 h, afforded after work-up and chromatography the title compound in 59% yield (22.6 mg). White solid. 1H NMR (500 MHz, CDCl3) δ 7.45 – 7.35 (m, 5H), 3.76 (s, 4H), 3.64 (s, 2H), 3.45 (s, 2H). 13C{1H} NMR (125 MHz, CDCl3) δ 170.6, 135.6, 130.1, 128.7, 127.3, 67.1, 48.4, 42.7. N-Butylbenzamide (3n), Transamidation of Amide (1o) with n-Butylamine. According to the general procedure, the reaction of tert-butyl benzoyl(benzyl)carbamate (62.3 mg, 0.20 mmol, 1.0 equiv) with n-butylamine (29.3 mg, 0.40 mmol, 2.0 equiv) in CH3CN (1.0 M) at room temperature for 15 h, afforded after work-up and chromatography the title compound in 89% yield (31.5 mg). Colorless oil. 1H

NMR (500 MHz, CDCl3) δ 7.78 – 7.73 (m, 2H), 7.48 (t, J = 7.3 Hz, 1H), 7.42 (t, J = 7.7 Hz, 2H),

6.17 (s, 1H), 3.45 (q, J = 6.6 Hz, 2H), 1.63 – 1.56 (m, 2H), 1.45 – 1.37 (m, 2H), 0.96 (t, J = 7.4 Hz, 3H). 13C{1H}

NMR (125 MHz, CDCl3) δ 167.8, 135.2, 131.6, 128.9, 127.2, 40.1, 32.1, 20.5, 14.1.

Morpholino(phenyl)methanone (3a), Transamidation of Amide (1o) with Morpholine. According to the general procedure, the reaction of tert-butyl benzoyl(benzyl)carbamate (47.0 mg, 0.20 mmol, 1.0 equiv) with morpholine (34.8 mg, 0.40 mmol, 2.0 equiv) in CH3CN (1.0 M) at 120 °C for 15 h, afforded after work-up and chromatography the title compound in 60% yield (22.9 mg). White solid. 1H NMR


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(500 MHz, CDCl3) δ 7.45 – 7.35 (m, 5H), 3.76 (s, 4H), 3.64 (s, 2H), 3.45 (s, 2H). 13C{1H} NMR (125 MHz, CDCl3) δ 170.6, 135.6, 130.1, 128.7, 127.3, 67.1, 48.4, 42.7. Synthesis of Tigan (4). According to the general procedure, an oven-dried reaction flask containing a stir bar was charged with amide (1p) (77.5 mg, 0.20 mmol, 1.0 equiv), amine (2n) (77.7 mg, 4.0 mmol, 2.0 equiv) and CH3CN (1.0 M). The reaction mixture was stirred at room temperature for 15 hours. After the indicated time, the solvent was removed under reduced pressure and the crude product was purified directly by chromatography on silica gel to afford Tigan (4) (73.0 mg, 94 %). White solid. 1H NMR (500 MHz, CDCl3) δ 7.29 – 7.26 (m, 2H), 7.00 (s, 2H), 6.93 – 6.88 (m, 2H), 6.29 (s, 1H), 4.56 (d, J = 5.6 Hz, 2H), 4.05 (t, J = 5.7 Hz, 2H), 3.88 (s, 6H), 3.87 (s, 3H), 2.72 (t, J = 5.7 Hz, 2H), 2.33 (s, 6H). 13C{1H} NMR (125 MHz, CDCl3) δ 167.3, 158.7, 153.5, 141.2, 130.7, 130.2, 129.6, 115.1, 104.7, 66.4, 61.2, 58.6, 56.6, 46.2, 44.0. Spectroscopic data matched those previously reported.30 Selectivity Studies – Amides. According to the general procedure, an oven-dried reaction flask equipped with a stir was charged with two amide substrates (each 0.20 mmol, 1.0 equiv), CH3CN (1.0 M) and amine (0.15 mmol, 0.75 equiv), and the reaction mixture was stirred at room temperature for 15 h. After the indicated time, the reaction mixture was diluted with EtOAc (15 mL), washed with HCl (aq., 1.0 N, 10 mL), the aqueous layer was extracted with EtOAc (2 × 15 mL), the organic layers were combined, dried, filtered, and concentrated. A sample was analyzed by 1H NMR (CDCl3, 500 MHz) and GC-MS to obtain conversion, yield and selectivity using internal standard and comparison with authentic samples. The observed selectivity is consistent with electrophilicity of the amide bond. Selectivity Studies – Amines. According to the general procedure, an oven-dried reaction flask equipped with a stir was charged with an amide substrate (0.10 mmol, 1.0 equiv), CH3CN (1.0 M) and two amine substrates (each 0.30 mmol, 3.0 equiv), and the reaction mixture was stirred at room temperature for 15 h. After the indicated time, the reaction mixture was diluted with EtOAc (15 mL), washed with HCl (aq., 1.0 N, 10 mL), the aqueous layer was extracted with EtOAc (2 × 15 mL), the organic layers were combined, dried, filtered, and concentrated. A sample was analyzed by 1H NMR 29 ACS Paragon Plus Environment


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(CDCl3, 500 MHz) and GC-MS to obtain conversion, yield and selectivity using internal standard and comparison with authentic samples. The observed selectivity is consistent with nucleophilic addition to the amide bond. Supporting Information. Copies of NMR spectra. This material is available free of charge via the Internet at http://pubs.acs.org. Author Information. Corresponding author: [email protected]

Acknowledgements. Rutgers University and the NSF (CAREER CHE-1650766) are gratefully acknowledged for support. The Bruker 500 MHz spectrometer was supported by the NSF-MRI grant (CHE-1229030). We thank Niccole Rodriguez (Rutgers University) for assistance. References (1) (a) Greenberg, A.; Breneman, C. M.; Liebman, J. F. The Amide Linkage: Structural Significance in Chemistry, Biochemistry and Materials Science; Wiley-VCH: New York, 2003. (b) Pattabiraman, V. R.; Bode, J. W. Rethinking Amide Bond Synthesis. Nature 2011, 480, 471-479. (c) Ruider, S.; Maulide, N. Strong Bonds Made Weak: Towards the General Utility of Amides as Synthetic Modules. Angew. Chem. Int. Ed. 2015, 54, 13856-13858. (2) For lead references on amide bonds in drug discovery and polymer chemistry, see: (a) Roughley, S. D.; Jordan, A. M. The Medicinal Chemist’s Toolbox: An Analysis of Reactions Used in the Pursuit of Drug Candidates. J. Med. Chem. 2011, 54, 3451-3479. (b) Kaspar, A. A.; Reichert, J. M. Future Directions for Peptide Therapeutics Development. Drug Discov. Today 2013, 18, 807-817. (c) Marchildon, K. Polyamides: Still Strong After Seventy Years. Macromol. React. Eng. 2011, 5, 22-54. (d) Brunton, L.; Chabner, B.; Knollman, B. Goodman and Gilman’s The Pharmacological Basis of Therapeutics; MacGraw-Hill: New York, 2010. For additional references on the importance of amides, see: (e) Valeur, E.; Bradley, M. Amide bond formation: beyond the myth of coupling reagents. Chem. 30 ACS Paragon Plus Environment

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Soc. Rev. 2009, 38, 606-631. (f) Lanigan, R. M.; Sheppard, T. D. Recent Developments in Amide Synthesis: Direct Amidation of Carboxylic Acids and Transamidation Reactions. Eur. J. Org. Chem. 2013, 7453-7465. (3) The development of new methods for the synthesis of amides has been identified as the key green chemistry research area: Constable, D. J. C.; Dunn, P. J.; Hayler, J. D.; Humphrey, G. R.; Leazer, Jr., J. L.; Linderman, R. J.; Lorenz, K.; Manley, J.; Pearlman, B. A.; Wells, A.; Zaks, A.; Zhang, T. Y. Key green chemistry research areas – a perspective from pharmaceutical manufacturers. Green Chem. 2007, 9, 411-420. (4) According to recent estimates more than three-quarters of drug candidates contains an amide bond: (a) Mullard, A. 2018 FDA drug approvals. Nat. Rev. Drug Discov. 2019, 18, 85-89. (b) Jarvis, L. M. FDA drug approvals hit all-time high. Chem. Eng. News Jan 2, 2019. (5) (a) Marcia de Figueiredo, R.; Suppo, J. S.; Campagne, J. M. Nonclassical routes for amide bond formation. Chem. Rev. 2016, 116, 12029-12122. (b) Loomis, W. D.; Stumpf, P. K. In Transamination and Transamidation (Nitrogen Metabolism); Allen, E. K., Ed.; Springer: Berlin, 1958. (c) Trost, B. M.; Fleming, I. Comprehensive Organic Synthesis; Pergamon Press: Oxford, 1991. (6) Pauling, L. The Nature of the Chemical Bond; Oxford University Press: London, 1940. (7) (a) Gonzalez-Rosende, M. E.; Castillo, E.; Lasri, J.; Sepulveda-Arques, J. Intermolecular and intramolecular transamidation reactions. Prog. React. Kinet. Mech. 2004, 29, 311-332. (b) Hoerter, J. M.; Otte, K. M.; Gellman, S. H.; Cui, Q.; Stahl, S. S. Discovery and mechanistic study of Al(III)catalyzed transamidation of tertiary amides. J. Am. Chem. Soc. 2008, 130, 647-654. (c) Stephenson, N. A.; Zhu, J.; Gellman, S. H.; Stahl, S. S. Catalytic transamidation reactions compatible with tertiary amide metathesis under ambient conditions. J. Am. Chem. Soc. 2009, 131, 10003-10008.


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(8) For reviews on N–C functionalization, see: (a) Shi, S.; Nolan, S. P.; Szostak, M. Well-Defined Palladium(II)-NHC (NHC = N-Heterocyclic Carbene) Precatalysts for Cross-Coupling Reactions of Amides and Esters by Selective Acyl CO–X (X = N, O) Cleavage. Acc. Chem. Res. 2018, 51, 25892599. (b) Liu, C.; Szostak, M. Decarbonylative Cross-Coupling of Amides. Org. Biomol. Chem. 2018, 16, 7998-8010. (c) Dander, J. E.; Garg, N. K. Breaking Amides using Nickel Catalysis. ACS Catal. 2017, 7, 1413-1423. (d) Takise, R.; Muto, K.; Yamaguchi, J. Cross-Coupling of Aromatic Esters and Amides. Chem. Soc. Rev. 2017, 46, 5864-5888, and references cited therein. (9) For studies on amide bond destabilization, see: Meng, G.; Shi, S.; Lalancette, R.; Szostak, R.; Szostak, M. Reversible Twisting of Primary Amides via Ground State N–C(O) Destabilization: Highly Twisted Rotationally Inverted Acyclic Amides. J. Am. Chem. Soc. 2018, 140, 727-734, and references cited therein. (10) For selected studies on amide cleavage, see: (a) Tani, K.; Stoltz, B. M. Synthesis and structural analysis of 2-quinuclidonium tetrafluoroborate. Nature 2006, 441, 731-734. (b) Elashai, H. E.; Raj, M. Site-selective chemical cleavage of peptide bonds. Chem. Commun. 2016, 52, 6304-6307. (c) Elashal, H. E.; Cohen, R. D.; Elashal, H. E.; Raj, M. Oxazolidinone-Mediated Sequence Determination of OneBead One-Compound Cyclic Peptide Libraries. Org. Lett. 2018, 20, 2374-2377. For additional studies on N–C cleavage, see: (d) Ito, M.; Sakaguchi, A.; Kobayashi, C.; Ikariya, T. Chemoselective Hydrogenation of Imides Catalyzed by Cp*Ru(PN) Complexes and Its Application to the Asymmetric Synthesis of Paroxetine. J. Am. Chem. Soc. 2007, 129, 290-291. (e) Kovalenko, O. O.; Volkov, A.; Adolfsson, H. Mild and Selective Et2Zn-Catalyzed Reduction of Tertiary Amides under Hydrosilylation Conditions. Org. Lett. 2015, 17, 446-449. (f) Shi, L.; Tan, X.; Long, J.; Xiong, X.; Yang, S.; Xue, P.; Lv, H.; Zhang, X. Direct Catalytic Hydrogenation of Simple Amides: A Highly Efficient Approach from Amides to Amines and Alcohols. Chem. Eur. J. 2017, 23, 546-548. (g) Kumar, A.; Janes, T.; Espinosa-Jalapa, N. A.; Milstein, D. Selective Hydrogenation of Cyclic Imides to Diols and Amines and Its Application in the Development of a Liquid Organic Hydrogen Carrier. J. Am. Chem. Soc. 2018, ACS Paragon Plus Environment

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Butyl Nicotinate-Directed Amide Cleavage as a Biomimic of Metallo-Exopeptidase Activity. ACS Catal. 2018, 8, 203-218, and references cited therein. (16) For leading references on metal-catalyzed amide activation, see: (a) Hie, L.; Nathel, N. F. F.; Shah, T. K.; Baker, E. L.; Hong, X.; Yang, Y. F.; Liu, P.; Houk, K. N.; Garg, N. K. Conversion of Amides to Esters by the Nickel-Catalysed Activation of Amide C–N Bonds. Nature 2015, 524, 79-83. (b) Meng, G.; Szostak, M. Sterically Controlled Pd-Catalyzed Chemoselective Ketone Synthesis via N– C Cleavage in Twisted Amides. Org. Lett. 2015, 17, 4364-4367. (c) Ni, S.; Zhang, W.; Mei, H.; Han, J.; Pan, Y. Ni-Catalyzed Reductive Cross-Coupling of Amides with Aryl Iodide Electrophiles via C–N Bond Activation. Org. Lett. 2017, 19, 2536-2539. (17) For selected examples of N–C bond cleavage, see: (a) Ni, S.; Li, C. X.; Mao, Y.; Han, J.; Wang, Y.; Yang, H.; Pan, Y. Ni-catalyzed deaminative cross-electrophile coupling of Katritzky salts with halides via C–N bond activation. Sci. Adv. 2019, 5, 9516. (b) Zhang, Z. B.; Ji, C. L.; Yang, C.; Chen, J.; Hong, X.; Xia, J. B. Nickel-Catalyzed Kumada Coupling of Boc-Activated Aromatic Amines via Nondirected Selective Aryl C–N Bond Cleavage. Org. Lett. 2019, 21, 1226-1231. (c) Yuan, Y. C.; Kamaraj, R.; Bruneau, C.; Labasque, T.; Roisnel, T.; Gramage-Doria, R. Unmasking Amides: Ruthenium-Catalyzed Protodecarbonylation of N-Substituted Phthalimide Derivatives. Org. Lett. 2017, 19, 6404-6407. (18) (a) Li, C. J.; Trost, B. M. Green chemistry for chemical synthesis. Proc. Natl. Acad. Sci. 2008, 105, 13197-13202. (b) Summerton, L.; Sneddon, H. F.; Jones, L. C.; Clark, J. H. Green and Sustainable Medicinal Chemistry: Methods, Tools and Strategies for the 21st Century Pharmaceutical Industry; RSC: Cambridge, 2016. (19) Dunetz, J. R.; Magano, J.; Weisenburger, G. A.; Large-Scale Applications of Amide Coupling Reagents for the Synthesis of Pharmaceuticals. Org. Process Res. Dev. 2016, 20, 140-177.


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