cyclization-reduction strategy.

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Combinatorial synthesis of nicotine analogs using an Ugi 4-CR/cyclization-reduction strategy† Luis A. Polindara-García and Alfredo Vazquez*

Received 11th April 2014, Accepted 11th July 2014

A practical one-pot synthesis of nicotine analogs from Ugi 4-CR/propargyl adducts is reported. This methodology allows the rapid construction of the pyrrolidine moiety present in nicotine through an intra-

DOI: 10.1039/c4ob00767k

molecular base-promoted 5-endo cycloisomerization process, followed by a reduction of the resulting

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mixture of 2- and 3-pyrrolines to afford nicotine analogs in good overall yields.

Introduction Recently, addiction to drugs has become a major medical and social concern. The addiction syndrome can be defined as a disease in which the body develops a physical dependence on the drug, resulting in compulsive and repetitive use despite the negative effects that drug abuse has on mental, physical and social health. Among the commonly used drugs are cocaine, nicotine, alcohol and amphetamines. It is well established that their mechanism of action involves multiple and complex neuronal modifications depending on the substance, the frequency of use, as well as physiological and genetic susceptibility. (S)-Nicotine (1, Fig. 1) is the main alkaloid found in tobacco and other plants from the Solanaceae family.1 This heterocyclic compound, comprising pyridine and pyrrolidine moieties, is responsible for the psychoactive effect and addic-

Fig. 1 Nicotine and molecules of biological importance to prevent/ deter smoking: nicotine 1, Zyban 2, Chantix 3, CNA 4 and a basic hapten design 5.

Departamento de Química Orgánica, Facultad de Química, Universidad Nacional Autónoma de México, Ciudad Universitaria, 04510 México, D.F., Mexico. E-mail: [email protected] † Electronic supplementary information (ESI) available: Copies of the 1H and 13 C NMR spectra for all the products. See DOI: 10.1039/c4ob00767k

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tion issues caused by tobacco smoking.2 According to estimates from the World Health Organization (WHO), consumption of tobacco was responsible for the death of ca. 100 million people in the twentieth century.3 In recent years, nicotine has received considerable attention from the scientific community, and substantial research thereon has been conducted in diverse scientific disciplines. These include the search for drugs to prevent/deter smoking,4 and its use as a starting material for the preparation of insecticides,5 and amino alcohols as catalysts for asymmetric synthesis.6 In addition, the pharmacological effects of nicotine and its derivatives on the central nervous system (CNS) and the potential thereof as drugs for the treatment of Parkinson’s disease, Alzheimer’s disease, Tourette syndrome, schizophrenia, attention deficit syndrome, hyperactivity disorder, epilepsy and depression have captured the attention of the synthetic community.7 Several strategies have evolved to attempt to treat the nicotine addiction problem. These include the use of the antidepressant ZYBAN® (2), or other drugs capable of binding specifically to the nicotine receptor, e.g. CHANTIX® (varenicline 3, Fig. 1). The use of this compound is however complicated by undesirable effects on the central nervous system (CNS).8 Other approaches, such as the use of skin patches, inhalers and chewing gums containing nicotine, have not proven to be efficient against tobacco addiction. In recent years, a new strategy called immunopharmacotherapy (vaccines) has emerged and is based on the generation of specific antibodies having the ability to trap the molecules of nicotine while they are in the bloodstream, preventing them from crossing the blood brain barrier (BBB) thereby minimizing their side effects on the CNS. This new technology has required the preparation of compounds structurally related to nicotine, such as CNA (4), reported by Janda and co-workers9 (Fig. 1). In order to obtain a prototype anti-nicotine vaccine, e.g. 5, nicotine, or analogues thereof, must be attached to a carrier protein using a spacer with a variable length that must possess a reactive center (e.g. a carboxyl functionality) that allows the

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formation of a covalent bond. The intensity of the immune response, quantified as the antibody concentration, depends on the type of carrier protein and hapten employed (i.e. nicotine molecule).10 The correct structure of nicotine was first proposed by Pinner11 and later corroborated by its synthesis.12 Subsequently, other syntheses of nicotine, or analogs thereof, both as racemates or enantiomerically pure forms, have been reported.13 Many strategies involve formation of the pyrrolidine ring from 3-substituted pyridines using several approaches.14–17 Conversely, the construction of the pyridine ring from a 2-substituted pyrrolidine (S-proline) has been reported.18 In recent years, the structural modification of nicotine has been thoroughly investigated by Comins.19–22 The Comins approach to prepare substituted nicotine derivatives was elegantly employed in the shortest enantioselective synthesis of Altinicline (5-ethynyl-nicotine),23 a drug employed for the treatment of Parkinson’s disease. Enantiopure (S)- and (R)-nicotine derivatives have also been obtained through resolution of racemic nicotine.24 For practical purposes, a racemic mixture of nicotine can be of use, and racemizations of the natural material have been developed.25 The broad interest in nicotine and its derivatives in different scientific areas encouraged us to pursue a synthetic strategy that would allow rapid and efficient preparation of nicotine derivatives, with different substitution patterns, by exploiting the Ugi reaction (a multicomponent reaction, MCR). The Ugi reaction has been extensively used in organic synthesis for the preparation of diverse structural motifs as well as natural products.26 To the best of our knowledge, this approach has not been reported for the preparation of nicotine derivatives. Herein, we disclose the first MCR approach for the 3 step synthesis of racemic nicotine analogs from commercially available raw materials. Inspired by the synthesis of α-aryl-2,3-dihydropyrroles reported by Miranda et al.,27 we designed a strategy for a one-pot synthesis of nicotine analogs 8 from Ugi 4-CR/propargyl adducts 6 via a cycloisomerization–reduction process (Scheme 1A).

Results and discussion According to the strategy designed to prepare nicotine analogs, three of the four components of the Ugi reaction can be modified to generate structural diversity, these being the carboxylic acid 12, the aldehyde 11, and the isocyanide 9 (Scheme 1). The nature of propargylamine (10) is fixed, because it is required to construct the pyrrolidine moiety. We commenced our studies with the synthesis of the model Ugi adduct 6b, obtained in 60% yield by the reaction of 3-pyridinecarboxaldehyde 11 with propargylamine 10, p-methoxybenzoic acid 12, and tert-butylisocyanide 9, in MeOH under microwave heating conditions (2 mol% InCl3, 50 °C, 100 W, 2 h). Reaction of a THF solution of 6b with potassium-tbutoxide (2.5 equiv.)27 at room temperature (1 h) gave a


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Scheme 1 (A) Cycloisomerization–reduction of Ugi-4CR/propargyl adducts. (B) Model study for the synthesis of nicotine analogs.

1.2 : 1 mixture of isomeric pyrrolines 7b and 7b′ in 80% yield (Scheme 1B). The reduction of the 7b/7b′ mixture was investigated under a variety of conditions (Table 1). Attempted reductions with Et3SiH in trifluoroacetic acid28 or ammonium formate in the presence of Pd/C29 both failed, and only the starting material was recovered (entries 1 and 2). Hydrogenation of a methanolic

Table 1 Optimization of the reaction conditions for the synthesis of nicotine analogsa

Entry

Pd

Mol (%)

[H]

Time (h)

Yieldb

1 2 3 4 5 6 7 8

— 5% Pd/C 10% Pd/C 10% Pd/C 20% Pd(OH)2 20% Pd(OH)2 20% Pd(OH)2 20% Pd(OH)2

— 100 10 10 10 10 10 20

Et3SiH CO2HNH4 H2 H2 H2 H2 H2 H2

7 4 24 13 6 7 7 5

— — — 61c,d 68d,e 70e, f 70e,d 75e, f

a

All reactions were carried out in MeOH at 25 °C (H2 = balloon), except for entry 1 (TFA, Et3SiH = 13 equiv.) and entry 2 (MeOH, 65 °C). b Yields correspond to isolated pure products. c The crude product was extracted with CH2Cl2 after the first reaction. d The final crude mixture was fractionated by flash column chromatography on silica gel. e No extraction is performed at the end of the first step. The crude mixture was used for the next reaction. f Purification by column chromatography was not required.

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solution (H2 balloon, 10% Pd/C) of the crude 7b/7b′ mixture was successful only if the KO-t-Bu from the previous reaction step was removed (cf. entries 3 and 4). Interestingly, the use of Pd(OH)2 instead of 10% Pd/C allowed direct hydrogenation of the crude KO-t-Bu containing the 7b/7b′ product mixture (entries 5–7). After extensive experimentation, the use of 20% Pd(OH)2 under a H2 atmosphere (balloon) in MeOH (0.1 M) at ambient temperature for 5 h was found to be optimal and provided the desired product as a white solid in 75% yield (entry 8). It is noteworthy that the use of column chromatography was not required and an essentially pure product was obtained after a simple work-up process.

Table 2

Scope of the methodologya

To explore the scope of the methodology, we carried out the synthesis of Ugi 4-CR/propargyl adducts using different benzoic acids, 3-pyridinecarboxaldehydes, isocyanides, and propargylamine 10. Adducts 6a–o were synthesized in moderate to good yields (29–74%) through the standard conditions used for the synthesis of compound 6b (Table 2, entries 1–15). The use of ortho and para substituted benzoic acids was investigated in order to establish the effect of substituents on the outcome of the Ugi reaction. The results shown in Table 2 indicate that the benzenoid substituents do not significantly affect the product yields (Ugi adduct yields shown in parentheses). In addition, the results shown in Table 3 indicate that there is, in fact, little if any restriction on the nature of the carboxylic acid, the corresponding Ugi adducts being obtained in moderate to good yields for a variety of aliphatic carboxylic acids (yields in parentheses). A good example of the potential of the strategy is illustrated using N-Boc-protected γ-aminobutyric acid, a bifunctional molecule (Table 3, entry 5). After removal of the Boc-protecting group, the amino functionality can be used to attach other molecules to the nicotine analog. In the case of the Ugi adduct 6r, the low yield was attributed to the low solubility of the carboxylic acid in the reaction medium (MeOH) (Table 3, entry 3).

Table 3

Isolated products. b In parenthesis, yields of the corresponding Ugi adducts. c 8a was isolated after the work-up. d 5.0 equiv. of t-BuOK were used. e Asymmetric induction was not observed after analysis of the 1 H NMR spectra (1 : 1 dr). f A 1 : 1.1 diastereomeric ratio was observed by 1H NMR. g A complex mixture was obtained after the cycloisomerization step.

Scope of the methodologya

a

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a

Isolated products. b In parenthesis, yields of the corresponding Ugi adducts. c 1.0 equiv. of t-BuOK was used. d 5.0 equiv. of t-BuOK were used.


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The effect of substituents on the nicotinaldehyde component was examined in a cursory manner only. Whereas a p-tolyl moiety at C-5 or a methoxy group at C-6 had little effect on the yield (Table 2, entries 10 and 11), a C-5 bromo substituent caused a significant diminution in the yield of the Ugi product (entry 12). The site of the aldehyde moiety in the pyridine nucleus had little effect on the Ugi product yield as indicated by the results for 2- and 4-formylpyridine (Table 3, entries 7 and 8). Interestingly, the Ugi adduct from 5-formylpyrimidine was obtained in only 17% yield (Table 3, entry 9). With regard to the isocyanide component of the Ugi reaction, the four aliphatic examples (t-butyl, cyclohexyl, (S)-(−)-α-methylbenzyl and (S)-1-(naphthalen-1-yl)ethyl) gave comparable adduct yields. In contrast, the Ugi adduct from 2-naphthylisocyanide was obtained in considerably reduced yield (34%, Table 2, entry 15). Further experiments will be required to rationalize this result. Initially, the Ugi adducts 6a–i derived from 9, 10, 11 and various benzoic acids were subjected to the “one-pot” cycloisomerization/reduction sequence using the conditions optimized for 6b (Table 2, entries 1–9). The corresponding nicotine analogues 8a–i were subsequently obtained in good yields (72–84%); Ugi adducts 6j–l, derived from substituted 3-pyridinecarboxaldehydes, were similarly subjected to the cyclization/reduction protocol with good success (Table 2, entries 10–12), however 6l underwent concomitant reductive debromination to give 8a because of the propensity of C–Br bonds of aromatic compounds to experience hydrogenolysis (Table 2, entry 12). Ugi adducts derived from isocyanides other than 9 were also investigated (entries 13–15). Cycloisomerization/reduction of adducts 6m (from cyclohexylisocyanide), 6n (from (S)-(−)-α-methylbenzylisocyanide) and 6n′ (from (S)-1-(1isocyanoethyl)naphthalene) provided the corresponding nicotine analogs 8m–n in good yields (Table 2, entries 13 and 14). In the case of 8n, asymmetric induction was not observed and a 1 : 1 mixture of diastereomers was obtained (1H NMR). However, in the case of 8n′ a diastereomeric ratio of 1 : 1.1 was observed by 1H NMR, indicating that there is a negligible asymmetric induction caused by the quiral isonitrile. Adduct 6o (from 2-naphthylisocyanide) gave an intractable mixture after cycloisomerization, and no further experiments were conducted with this substrate (Table 2, entry 15). Table 3 shows that Ugi adducts derived from both aliphatic and aromatic carboxylic acids and pyridine carboxaldehydes with different substitution patterns can afford nicotine analogs in good yields (entries 1–8). However, the Ugi adduct derived from pyrimidine carboxaldehyde provided the corresponding nicotine analog 8x in lower yield (entry 9). In most cases, 2.5 equivalents of a base were used in order to obtain the best results in the shortest period of time. Lesser amounts of the base resulted in increased reaction times and diminished product yields. In the case of the aliphatic carboxylic acids 8t and 8u, the cycloisomerization failed with 2.5 equivalents of the base, but was successful with 5 equivalents of it, presumably because of the presence of additional C-α acidic hydrogen atoms, and in the case of 8t, an extra


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Scheme 2

Plausible mechanism for the cycloisomerization process.

Scheme 3

N-Dealkylation of 8a.

NH group. It is noteworthy that in the case of 8s, 8t and 8u (Table 3, entries 4, 5 and 6), despite the possibility of other cyclization products (i.e. six membered rings) only the products shown in Tables 2 and 3 were observed. A plausible mechanism for the base-mediated cycloisomerization process of Ugi 4-CR/propargyl adducts that allows the formation of the 2- and 3-pyrroline mixture is presented in Scheme 2 and can be rationalized as follows: initially, the dianionic intermediate30 A would be generated using 2.5 equivalents of a base, and then two possible scenarios can be envisioned: (1) a rapid 1,5 hydrogen shift between the amide anion and the proton of the methylene moiety to form the anionic allenamide31 B, which then reacts in an intramolecular fashion to give the 2-pyrroline via 5-endo-trig cycloisomerization,27 and (2) an intramolecular attack of the enolate onto the terminal sp carbon of the alkyne would generate the dianionic intermediate C via a 5-endo-dig cycloisomerization, which after protonation would furnish the expected 3-pyrroline32 (Scheme 2). Finally, selective dealkylation of the N-tert-Bu group in 8a using the BF3·2CH3COOH complex was achieved under reported conditions33 to obtain the nicotine–amide analog 13a in 40% yield. This result opens the door for further functionalization of the 2′-position of the nicotine analogs, allowing access to derivatives previously not described in the literature (Scheme 3).

Experimental General information All reagents and solvents were obtained from Sigma-Aldrich and were used without further purification. Methanol was dried over magnesium/iodide and stored over 4 Å molecular sieves, and THF was dried over sodium benzophenone ketyl under a N2 atmosphere prior to use. The progress of the reac-

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tions was monitored by TLC using precoated silica gel Kieselgel 60 F254 plates; the spots were visualized under UV light (254 nm), or with phosphomolybdic acid and vanillin. Flash column chromatography (FCC) was performed using Macherey-Nagel silica gel 60 (230–400 mesh). Microwaveassisted reactions were performed using a CEM Discover Synthesis™ unit (CEM corp., Matthews, NC) with a monomodal open-vessel system. Melting points (mp) were determined on a Fisher-Johns instrument and are uncorrected. NMR spectra were collected on an Agilent MR (400 MHz) and Agilent Unity Inova (300 MHz) spectrometer, using tetramethylsilane (TMS) as an internal standard. The 1H NMR chemical shifts and coupling constants were determined assuming first order behavior. Multiplicity is indicated by one or more of the following: s (singlet), br s (broad singlet), d (doublet), t (triplet), q (quartet), and m (multiplet). High-resolution mass spectra were recorded on a Jeol SX-102A instrument. IR spectra were recorded on a Perkin-Elmer Spectrum 400 FT-IR/FIR spectrometer with ATR. Synthesis of the starting materials (S)-N-(1-(Naphthalen-1-yl)ethyl)formamide. A mixture of (S)-(−)-1-(1-naphthyl)-ethylamine hydrochloride (0.501 g, 2.41 mmol), Et3N (0.369 mL, 2.65 mmol) and ethyl formate (1.785 g, 24.1 mmol) was heated at 100 °C under microwave irradiation (100 W) for 1 hour. The reaction mixture was concentrated under reduced pressure and purified by flash column chromatography (50% EtOAc–hexanes) to give a white solid (83%). Rf 0.33 (50% EtOAc–hexanes), mp: 112–113 °C. 1H NMR (300 MHz, CDCl3) δ ( ppm): 8.14 (s, 1H), 8.12–8.03 (m, 1H), 7.87 (ddd, J = 7.4, 1.7, 0.8 Hz, 1H), 7.80 (dd, J = 8.0, 1.2 Hz, 1H), 7.60–7.39 (m, 4H), 6.01 (m, 1H), 5.83 (br s, 1H), 1.69 (d, J = 6.8 Hz, 3H). 13C NMR (75 MHz, CDCl3) δ ( ppm): 160.1, 137.6, 134.1, 131.1, 129.0, 128.7, 126.8, 126.1, 125.3, 123.4, 122.8, 43.6, 20.8. IR v (cm−1): 728, 772, 794, 1120, 1172, 1251, 1393, 1540, 1655, 1864, 1915, 2882, 2971, 3290. HRMS (EI+) calcd for C13H13NO: [M] 199.0997, found: 199.0993. (S)-1-(1-Isocyanoethyl)naphthalene.34 To a solution of (S)-N(1-(naphthalen-1-yl)ethyl)formamide (0.152 g, 0.767 mmol) in CH2Cl2 (7.6 mL) was added N-methylmorpholine (0.043 mL, 0.40 mmol). The resulting mixture was cooled at −78 °C; then, triphosgene (0.020 g, 0.07 mmol) was added in one portion and the reaction mixture was stirred at this temperature for 10 min. The solution was then warmed to −30 °C and the stirring was continued at this temperature for 3 h. The reaction mixture was warmed to room temperature, quenched by addition of H2O (10 mL) and extracted with CH2Cl2 (3 × 10 mL). The organics were combined, washed with brine, dried (Na2SO4) and concentrated in vacuo. The crude product was purified by flash column chromatography (10% EtOAc– hexanes) to give a yellow oil (74%). Rf 0.35 (10% EtOAc– hexanes). 1H NMR (400 MHz, CDCl3) δ ( ppm): 7.94–7.84 (m, 3H), 7.75 (d, J = 7.2 Hz, 1H), 7.58 (ddd, J = 8.5, 6.9, 1.6 Hz, 1H), 7.53 (ddd, J = 8.2, 6.9, 1.3 Hz, 2H), 5.64–5.53 (m, 1H), 1.85 (m, 3H). 13C NMR (100 MHz, CDCl3) δ ( ppm): 134.0, 129.4, 129.2, 127.0, 126.1, 125.7, 123.2, 122.1, 51.2, 24.3. IR v (cm−1): 413,

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433, 499, 773, 798, 1110, 1170, 1257, 1378, 1447, 1513, 1599, 1658, 1948, 2137, 2988, 3052. HRMS (EI+) calcd for C13H10N: [M − 1] 180.0813, found: 180.0818. This compound was used for the synthesis of the Ugi adduct 6n′. 5-(p-Tolyl)nicotinaldehyde (11k).35 To a solution of 5-bromonicotinaldehyde (0.093 g, 0.50 mmol) in toluene (3.35 mL) was added an aqueous solution of Na2CO3 (1.57 mL, 2.0 M) followed by 4-methylboronic acid (0.081 g, 0.60 mmol) dissolved in EtOH (1.57 mL). The resulting mixture was deoxygenated (×3) under vacuum and nitrogen (Schlenk tube). Then, Pd(PPh3)4 (0.023 g, 4 mol%) was added under a nitrogen atmosphere, and the mixture was stirred at 100 °C (oil bath) until completion was indicated by TLC (16 h). The reaction mixture was cooled to room temperature, quenched by addition of H2O (10 mL) and extracted with EtOAc (3 × 10 mL). The organics were combined, washed with brine, dried (Na2SO4) and concentrated in vacuo. The crude product was purified by flash column chromatography (30% EtOAc– hexanes) to give 5-( p-tolyl)nicotinaldehyde 11k as a pale yellow solid (0.069 g, 71%). Rf 0.5 (EtOAc–hexanes 7 : 3), mp: 54–55 °C. 1H NMR (300 MHz, CDCl3) δ ( ppm): 10.19 (s, 1H), 9.07 (d, J = 2.3 Hz, 1H), 9.02 (d, J = 2.0 Hz, 1H), 8.33 (dd, J = 2.2 Hz, 1H), 7.53 (d, J = 8.2 Hz, 2H), 7.33 (dd, J = 8.4, 0.8 Hz, 2H), 2.43 (s, 3H). 13C NMR (75 MHz, CDCl3) δ ( ppm): 191.0, 153.3, 150.6, 139.1, 137.3, 133.5, 133.5, 131.5, 130.2, 127.2, 21.3. IR v (cm−1) 562, 702, 725, 816, 885, 1175, 1301, 1381, 1576, 1704, 1908, 2853, 2920, 3028. HRMS (FAB+, M+) calcd for C13H12NO: [M + 1] 198.0919, found: 198.0913. This compound was used for the synthesis of the Ugi adduct 6k. 4-((tert-Butoxycarbonyl)amino)butanoic acid (12t). To a cooled (0 °C) solution of 4-aminobutanoic acid (1.00 g, 9.69 mmol) in 1 : 1 dioxane–water (38.5 mL, 0.25 M), (Boc)2O (2.33 g, 10.66 mmol) and Et3N (2.02 mL, 14.53 mmol) were successively added and the resulting solution was stirred at 0 °C for 30 minutes. The reaction mixture was warmed to room temperature and stirred until completion was indicated by TLC (22 h). The reaction mixture was concentrated in vacuo and the crude product was dissolved in EtOAc (20 mL) and water (20 mL), acidified to pH 1.0 with 10% HCl (v/v) and extracted with EtOAc (3 × 40 mL). The organics were combined, washed with brine, dried (Na2SO4) and concentrated in vacuo to give 4-((tert-butoxycarbonyl)amino)butanoic acid 12t as an orange oil (1.922 g, 97%). 1H NMR (400 MHz, CDCl3) δ (ppm): 4.70 (br s, 1H), 3.19 (q, J = 6.7 Hz, 2H), 2.40 (t, J = 7.2 Hz, 2H), 1.88–1.76 (m, 2H), 1.44 (s, 9H). 13C NMR (75 MHz, CDCl3) 178.6, 156.4, 79.7, 39.9, 31.4, 28.5, 25.3. IR v (cm−1): 652, 1010, 1159, 1276, 1365, 1537, 1680, 1715, 2981, 3205. HRMS (FAB+, M+) calcd for C9H18NO4: [M + 1] 204.1236, found: 204.1241. This compound was used for the synthesis of the Ugi adduct 6t.

General procedure for the synthesis of Ugi adducts 6a–x A solution of the carboxylic acid (1.0 eq.), nicotinaldehyde (1.0 eq.), propargylamine 10 (1.0 eq.), isocyanide (1.0 eq.), indium(III) chloride (2 mol%) in anhydrous MeOH (0.33 M) was heated to 50 °C under microwave irradiation (100 W) for


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2 hours. The reaction mixture was concentrated under reduced pressure and purified by flash column chromatography. N-(2-(tert-Butylamino)-2-oxo-1-( pyridin-3-yl)ethyl)-N-( prop-2yn-1-yl)benzamide (6a). Using the general procedure, this compound was obtained as a white solid in 52% yield (1.5 mmol scale), after purification by flash column chromatography (EtOAc). Rf 0.30 (EtOAc), mp: 163–164 °C. 1H NMR (400 MHz, CDCl3) δ ( ppm): 8.67 (br s, 1H), 8.60 (dd, J = 4.8, 1.6 Hz, 1H), 7.89 (br s, 1H), 7.60 (dd, J = 7.8, 1.8 Hz, 2H), 7.50–7.40 (m, 3H), 7.33 (ddd, J = 7.9, 4.8, 0.8 Hz, 1H), 6.12 (s, 1H), 5.85 (br s, 1H), 4.24 (dd, J = 18.4, 2.5 Hz, 1H), 4.09–4.03 (m, 1H), 2.05 (t, J = 2.4 Hz, 1H), 1.40 (s, 9H). 13C NMR (100 MHz, CDCl3) δ ( ppm): 172.5, 167.7, 151.2, 149.8, 137.3, 134.9, 131.0, 130.8, 128.8, 127.3, 123.7, 79.4, 72.7, 61.2, 52.1, 38.4, 28.8. IR v (cm−1): 571, 634, 661, 702, 732, 791, 1175, 1218, 1293, 1325, 1399, 1433, 1549, 1641, 1655, 2124, 2930, 2973, 3038, 3073, 3299. HRMS (FAB+, M+) calcd for C21H24N3O2: [M + 1] 350.1869, found: 350.1871. N-(2-(tert-Butylamino)-2-oxo-1-(pyridin-3-yl)ethyl)-4-methoxyN-(prop-2-yn-1-yl)benzamide (6b). Using the general procedure, this compound was obtained as a pale yellow solid in 60% yield (3.0 mmol scale) after purification by flash column chromatography (EtOAc). Rf 0.21 (EtOAc), mp: 130–132 °C. 1 H NMR (400 MHz, CDCl3) δ ( ppm): 8.69 (br s, 1H), 8.61 (dd, J = 4.9, 1.6 Hz, 1H), 8.05 (d, J = 8.9 Hz, 1H), 7.89 (d, J = 7.8 Hz, 1H), 7.62 (d, J = 8.7 Hz, 2H), 7.34 (ddd, J = 8.0, 4.8, 0.8 Hz, 1H), 6.93 (d, J = 8.7 Hz, 2H), 6.23 (s, 1H), 5.81 (s, 1H), 4.28 (dd, J = 18.5, 2.4 Hz, 1H), 4.08 (dd, J = 18.5, 2.5 Hz, 1H), 3.84 (s, 3H), 2.09 (t, J = 2.4 Hz, 1H), 1.40 (s, 9H). 13C NMR (100 MHz, CDCl3) δ ( ppm): 172.4, 168.0, 161.7, 151.0, 149.5, 137.4, 132.1, 131.2, 129.5, 123.7, 114.0, 79.6, 72.9, 61.8, 55.5, 52.1, 38.5, 28.8. IR v (cm−1): 712, 837, 1027, 1179, 1248, 1302, 1365, 1400, 1514, 1569, 1607, 1633, 1682, 1899, 2116, 2965, 3022, 3219, 3285. HRMS (FAB+, M+) calcd for C22H26N3O3: [M + 1] 380.1974, found: 380.1980. N-(2-(tert-Butylamino)-2-oxo-1-( pyridin-3-yl)ethyl)-4-ethyl-N( prop-2-yn-1-yl)benzamide (6c). Using the general procedure, this compound was obtained as a pale yellow solid in 36% yield (1.0 mmol scale) after purification by flash column chromatography (50% EtOAc–hexanes). Rf 0.40 (EtOAc), mp: 134–136 °C. 1H NMR (400 MHz, CDCl3) δ ( ppm): 8.69 (br s, 1H), 8.62 (dd, J = 4.8, 1.6 Hz, 1H), 7.89 (d, J = 7.9 Hz, 1H), 7.34 (ddd, J = 8.0, 4.9, 0.8 Hz, 1H), 7.31–7.26 (m, 1H), 7.21 (d, J = 2.0 Hz, 1H), 6.89 (d, J = 8.3 Hz, 1H), 6.16 (s, 1H), 5.83 (s, 1H), 4.31 (dd, J = 18.5, 2.4 Hz, 1H), 4.12 (ddd, J = 18.4, 2.5, 0.6 Hz, 1H), 3.92 (s, 3H), 3.90 (s, 3H), 2.08 (s, 1H), 1.40 (s, 9H). 13 C NMR (100 MHz, CDCl3) δ ( ppm): 172.2, 168.0, 151.3, 151.2, 149.6, 148.9, 137.4, 131.2, 126.9, 123.7, 121.0, 111.0, 110.8, 80.0, 72.7, 61.6, 56.1, 56.1, 52.1, 38.6, 28.8. IR v (cm−1): 709, 749, 1026, 1131, 1179, 1226, 1265, 1364, 1403, 1517, 1545, 1583, 1606, 1686, 2110, 2936, 2963, 2998, 3240, 3307. HRMS (FAB+, M+) calcd for C23H28N3O4: [M + 1] 410.2080, found: 410.2085. N-(2-(tert-Butylamino)-2-oxo-1-(pyridin-3-yl)ethyl)-4-(dimethylamino)-N-(prop-2-yn-1-yl)benzamide (6d). Using the general procedure, this compound was obtained as a pale yellow solid


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in 37% yield (1.0 mmol scale) after purification by flash column chromatography (50% EtOAc–hexanes). Rf 0.15 (50% EtOAc–hexanes), mp: 136–138 °C. 1H NMR (400 MHz, CDCl3) δ ( ppm): 8.65 (br s, 1H), 8.56 (dd, J = 4.8, 1.6 Hz, 1H), 7.86 (d, J = 7.8 Hz, 1H), 7.58 (d, J = 8.8 Hz, 2H), 7.29 (dd, J = 7.8, 4.8 Hz, 1H), 6.67 (dd, J = 8.8, 1.4 Hz, 2H), 6.59 (s, 1H), 5.76 (s, 1H), 4.33 (dd, J = 18.3, 2.1 Hz, 1H), 4.09 (d, J = 18.3 Hz, 1H), 3.01 (s, 6H), 2.15 (t, J = 2.4 Hz, 1H), 1.40 (s, 9H). 13C NMR (100 MHz, CDCl3) δ ( ppm): 172.9, 168.3, 152.3, 151.0, 149.4, 137.1, 131.5, 129.7, 123.4, 121.0, 111.2, 79.9, 72.9, 62.6, 51.9, 40.2, 38.7, 28.8. IR v (cm−1): 566, 621, 710, 827, 943, 1170, 1187, 1225, 1254, 1361, 1398, 1440, 1527, 1548, 1598, 1672, 1682, 1907, 2108, 2923, 2965, 3238, 3296. HRMS (FAB+, M+) calcd for C23H29N4O2: [M + 1] 393.2291, found: 393.2285. N-(2-(tert-Butylamino)-2-oxo-1-(pyridin-3-yl)ethyl)-2-methyl-N(prop-2-yn-1-yl)benzamide (6e). Using the general procedure, this compound was obtained as a pale yellow solid in 60% yield (1.0 mmol scale) after purification by flash column chromatography (20% EtOAc–hexanes). Rf 0.25 (20% EtOAc– hexanes), mp: 157–159 °C. 1H NMR (400 MHz, CDCl3) δ ( ppm): 8.71 (s, 1H), 8.59 (d, J = 4.2 Hz, 1H), 7.96 (d, J = 8.8 Hz, 1H), 7.36–7.20 (m, 5H), 6.34 (br s, 1H), 6.13 (s, 1H), 4.13 (d, J = 18.4 Hz, 1H), 3.91 (d, J = 19.0 Hz, 1H), 2.35 (s, 3H), 1.94 (s, 1H), 1.39 (s, 9H). 13C NMR (100 MHz, CDCl3) δ ( ppm): 172.5, 167.7, 151.2, 149.7, 137.4, 135.0, 134.9, 130.9, 130.8, 129.6, 125.9, 125.8, 123.6, 78.8, 72.5, 59.6, 52.0, 37.7, 28.7, 19.2. IR v (cm−1): 454, 565, 582, 625, 658, 744, 776, 945, 1179, 1224, 1298, 1331, 1362, 1404, 1443, 1556, 1599, 1620, 1677, 1923, 2119, 2970, 3083, 3275. HRMS (FAB+, M+) calcd for C22H26N3O2: [M + 1] 364.2025, found: 364.2020. N-(2-(tert-Butylamino)-2-oxo-1-( pyridin-3-yl)ethyl)-4-ethyl-N( prop-2-yn-1-yl)benzamide (6f ). Using the general procedure, this compound was obtained as a pale yellow solid in 50% yield (1.0 mmol scale) after purification by flash column chromatography (50% EtOAc–hexanes). Rf 0.25 (50% EtOAc– hexanes), mp: 125–127 °C. 1H NMR (400 MHz, CDCl3) δ ( ppm): 8.62 (br s, 1H), 8.57 (dd, J = 4.9, 1.8 Hz, 1H), 7.87 (s, 1H), 7.52 (d, J = 7.7 Hz, 2H), 7.31 (ddd, J = 8.0, 4.9, 1.0 Hz, 1H), 7.25 (d, J = 7.6 Hz, 2H), 6.39 (s, 1H), 5.85 (br s, 1H), 4.27 (dd, J = 18.4, 2.5 Hz, 1H), 4.08 (dd, J = 18.4, 2.5 Hz, 1H), 2.68 (q, J = 7.6 Hz, 2H), 2.05 (s, 1H), 1.39 (s, 9H), 1.25 (t, J = 7.6 Hz, 3H). 13 C NMR (100 MHz, CDCl3) δ ( ppm): 172.6, 167.9, 151.1, 149.6, 147.3, 137.2, 132.1, 131.1, 128.1, 127.4, 123.6, 79.6, 72.7, 61.2, 52.0, 38.4, 28.9, 28.7, 15.4. IR v (cm−1): 706, 841, 943, 1138, 1257, 1362, 1393, 1437, 1555, 1641, 1679, 2115, 2934, 2967, 3230, 3300. HRMS (FAB+, M+) calcd for C23H28N3O2: [M + 1] 378.2182, found: 378.2188. N-(2-(tert-Butylamino)-2-oxo-1-(pyridin-3-yl)ethyl)-2-chloro-N(prop-2-yn-1-yl)benzamide (6g). Using the general procedure, this compound was obtained as a white solid in 68% yield (1.0 mmol scale) after purification by flash column chromatography (50% EtOAc–hexanes). Rf 0.35 (50% EtOAc–hexanes), mp: 124–126 °C. 1H NMR (400 MHz, CDCl3) δ ( ppm): 8.71 (s, 1H), 8.58 (s, 1H), 7.97 (br s, 1H), 7.51–7.23 (m, 5H), 6.63–5.92 (m, 2H), 4.45–3.70 (m, 2H), 2.43–1.85 (m, 1H), 1.40 (s, 9H). 13 C NMR (100 MHz, CDCl3) δ ( ppm): 169.3, 167.0, 151.4, 149.7,

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137.4, 134.6, 131.0, 129.9, 128.1, 127.3, 123.5, 78.2, 73.2, 59.3, 52.1, 37.1, 28.7. IR v (cm−1): 572, 619, 650, 711, 752, 772, 1027, 1058, 1146, 1187, 1222, 1328, 1405, 1442, 1478, 1556, 1644, 1680, 2122, 2967, 3302. HRMS (FAB+, M+) calcd for C21H23ClN3O2: [M + 1] 384.1479, found: 384.1483. N-(2-(tert-Butylamino)-2-oxo-1-( pyridin-3-yl)ethyl)-2-fluoro-N( prop-2-yn-1-yl)benzamide (6h). Using the general procedure, this compound was obtained as a pale orange solid in 62% yield (1.0 mmol scale) after purification by flash column chromatography (50% EtOAc–hexanes). Rf 0.15 (50% EtOAc– hexanes), mp: 152–154 °C. 1H NMR (400 MHz, CDCl3) δ ( ppm): 8.69 (br s, 1H), 8.58 (d, J = 4.4 Hz, 1H), 7.98–7.88 (m, 1H), 7.51–7.37 (m, 2H), 7.33 (dd, J = 8.0, 4.8 Hz, 1H), 7.23 (m, 1H), 7.15 (m, 1H), 6.34 (br s, 1H), 6.09 (s, 1H), 4.13 (d, J = 18.6 Hz, 1H), 3.96 (d, J = 18.7 Hz, 1H), 2.05 (s, 1H), 1.40 (s, 9H). 13C NMR (100 MHz, CDCl3) δ ( ppm): 167.8, 167.1, 159.7, 157.2, 151.0, 149.7, 137.4, 132.1, 132.1, 130.6, 128.8, 124.8, 123.6, 123.5, 123.3, 116.3, 116.11, 78.2, 73.2, 60.3, 52.1, 37.6, 28.7. IR v (cm−1): 573, 630, 681, 757, 780, 832, 1177, 1218, 1296, 1322, 1401, 1435, 1547, 1613, 1639, 1656, 2124, 2975, 3269, 3297. HRMS (FAB+, M+) calcd for C21H23FN3O2: [M + 1] 368.1774, found: 368.1766. N-(2-(tert-Butylamino)-2-oxo-1-( pyridin-3-yl)ethyl)-N-( prop-2yn-1-yl)-4-(trifluoromethyl)benzamide (6i). Using the general procedure, this compound was obtained as an orange solid in 64% yield (1.0 mmol scale) after purification by flash column chromatography (50% EtOAc–hexanes). Rf 0.20 (50% EtOAc– hexanes), mp: 167–169 °C. 1H NMR (400 MHz, CDCl3) δ ( ppm): 8.66 (br s, 1H), 8.62 (dd, J = 5.2, 1.6 Hz, 1H), 7.89 (s, 1H), 7.77–7.66 (m, 4H), 7.42–7.31 (m, 1H), 6.09 (br s, 1H), 5.99 (br s, 1H), 4.24 (d, J = 18.6 Hz, 1H), 4.03 (d, J = 17.3 Hz, 1H), 2.05–1.92 (m, 1H), 1.39 (s, 9H). 13C NMR (100 MHz, CDCl3) δ ( ppm): 171.2, 167.5, 151.4, 150.0, 138.5, 137.4, 133.0, 132.7, 132.4, 132.1, 130.7, 127.7, 125.8, 125.7, 123.8, 79.1, 72.9, 60.2, 52.3, 38.2, 28.7. IR v (cm−1): 636, 712, 850, 1064, 1118, 1163, 1256, 1326, 1414, 1536, 1644, 1678, 1928, 2127, 2974, 3062, 3223, 3329. HRMS (FAB+, M+) calcd for C22H23F3N3O2: [M + 1] 418.1742, found: 418.1737. N-(2-(tert-Butylamino)-1-(6-methoxypyridin-3-yl)-2-oxoethyl)N-( prop-2-yn-1-yl)benzamide (6j). Using the general procedure, this compound was obtained as a white solid in 59% yield (1.0 mmol scale) after purification by flash column chromatography (20% EtOAc–hexanes). Rf 0.15 (20% EtOAc– hexanes), mp: 142–144 °C. 1H NMR (400 MHz, CDCl3) δ ( ppm): 8.22 (br s, 1H), 7.75 (br s, 1H), 7.63–7.53 (m, 2H), 7.52–7.39 (m, 3H), 6.77 (d, J = 8.6 Hz, 1H), 6.01 (s, 1H), 5.80 (br s, 1H), 4.20 (ddd, J = 18.5, 2.5, 1.0 Hz, 1H), 4.04 (dd, J = 18.3, 2.5 Hz, 1H), 3.95 (s, 3H), 2.07 (td, J = 2.5, 1.0 Hz, 1H), 1.39 (s, 9H). 13C NMR (100 MHz, CDCl3) δ ( ppm): 172.4, 168.1, 164.4, 148.4, 140.2, 135.2, 130.6, 128.7, 127.2, 123.5, 111.1, 79.7, 72.5, 60.5, 53.7, 52.0, 38.2, 28.8. IR v (cm−1): 570, 656, 699, 1030, 1216, 1290, 1388, 1318, 1388, 1431, 1493, 1540, 1639, 1659, 2117, 2977, 3256, 3306. HRMS (FAB+, M+) calcd for C22H26N3O3: [M + 1] 380.1974, found: 380.1974. N-(2-(tert-Butylamino)-2-oxo-1-(5-(p-tolyl)pyridin-3-yl)ethyl)-N(prop-2-yn-1-yl)benzamide (6k). Using the general procedure,

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this compound was obtained as a pale yellow solid in 69% yield (0.65 mmol scale) after purification by flash column chromatography (50% EtOAc–hexane). Rf 0.40 (50% EtOAc– hexanes), mp: 68–70 °C. 1H NMR (400 MHz, CDCl3) δ ( ppm): 8.83 (br s, 1H), 8.64 (s, 1H), 8.16–8.01 (m, 1H), 7.61 (d, J = 6.2 Hz, 2H), 7.52–7.38 (m, 5H), 7.29 (dd, J = 7.8, 0.8 Hz, 2H), 6.27 (s, 1H), 6.00 (br s, 1H), 4.30 (dd, J = 18.5, 2.5 Hz, 1H), 4.16–4.07 (m, 1H), 2.41 (s, 3H), 2.04 (s, 1H), 1.41 (s, 9H). 13 C NMR (100 MHz, CDCl3) δ ( ppm): 172.6, 167.8, 149.0, 147.8, 138.6, 136.7, 135.8, 134.9, 134.3, 132.9, 131.0, 130.7, 130.0, 128.7, 128.4, 127.3, 127.1, 79.6, 72.7, 60.5, 52.1, 38.6, 28.8, 21.3. IR v (cm−1): 661, 699, 712, 1140, 1184, 1223, 1252, 1364, 1394, 1448, 1546, 1629, 1681, 1903, 2117, 2966, 3299. HRMS (FAB+, M+) calcd for C28H30N3O2: [M + 1] 440.2338, found: 440.2340. N-(1-(5-Bromopyridin-3-yl)-2-(tert-butylamino)-2-oxoethyl)-N( prop-2-yn-1-yl)benzamide (6l). Using the general procedure, this compound was obtained as a pale yellow solid in 34% yield (1.0 mmol scale) after purification by flash column chromatography (40% EtOAc–hexanes). Rf 0.65 (50% EtOAc– hexanes), mp: 177–179 °C. 1H NMR (400 MHz, CDCl3) δ ( ppm): 8.68 (d, J = 2.2 Hz, 1H), 8.63 (br s, 1H), 8.13–8.03 (m, 1H), 7.67–7.56 (m, 2H), 7.50–7.42 (m, 3H), 6.34 (br s, 1H), 5.89 (br s, 1H), 4.28 (dd, J = 18.5, 2.5 Hz, 1H), 4.09 (dd, J = 18.6, 2.5 Hz, 1H), 2.13 (t, J = 2.5 Hz, 1H), 1.39 (s, 9H). 13C NMR (100 MHz, CDCl3) δ ( ppm): 172.6, 167.2, 150.7, 148.9, 140.1, 134.5, 133.2, 132.7, 131.0, 130.1, 128.8, 127.3, 120.8, 79.3, 73.2, 60.2, 52.2, 38.7, 28.7. IR v (cm−1): 639, 663, 697, 936, 1183, 1220, 1253, 1359, 1411, 1449, 1542, 1601, 1618, 1680, 2555, 2934, 2967, 3063, 3226, 3303, 3315. HRMS (FAB+, M+) calcd for C21H23BrN3O2: [M + 1] 428.0974, found: 428.0977. N-(2-(Cyclohexylamino)-2-oxo-1-( pyridin-3-yl)ethyl)-N-( prop2-yn-1-yl)benzamide (6m). Using the general procedure, this compound was obtained as a pale yellow solid in 59% yield (1.0 mmol scale) after purification by flash column chromatography (50% EtOAc–hexanes). Rf 0.25 (50% EtOAc–hexanes), mp: 109–111 °C. 1H NMR (400 MHz, CDCl3) δ ( ppm): 8.67 (s, 1H), 8.60 (d, J = 4.9 Hz, 1H), 7.88 (s, 1H), 7.59 (d, J = 7.2 Hz, 2H), 7.51–7.40 (m, 3H), 7.33 (dd, J = 8.0, 4.8 Hz, 1H), 6.33 (d, J = 8.1 Hz, 1H), 5.92 (s, 1H), 4.26 (dd, J = 18.6, 2.4 Hz, 1H), 4.06 (dd, J = 18.5, 2.5 Hz, 1H), 3.87 (ddd, J = 11.4, 8.2, 4.0 Hz, 1H), 2.07 (s, 1H), 1.95 (ddd, J = 17.7, 13.6, 4.4 Hz, 2H), 1.71 (ddd, J = 13.9, 9.4, 4.2 Hz, 2H), 1.61 (dd, J = 12.7, 4.0 Hz, 1H), 1.47–1.30 (m, 2H), 1.19 (ddd, J = 20.1, 11.7, 3.9 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ ( ppm): 172.6, 167.5, 151.1, 149.8, 137.2, 134.9, 130.9, 130.8, 128.8, 127.3, 123.7, 79.4, 72.9, 61.0, 48.9, 38.3, 33.0, 32.9, 25.6, 24.9, 24.8. IR v (cm−1) 622, 707, 923, 943, 1140, 1199, 1247, 1363, 1403, 1447, 1552, 1637, 2117, 2854, 2930, 3086, 3224, 3268. HRMS (FAB+, M+) calcd for C23H26N3O2: [M + 1] 376.2025, found: 376.2028. N-(2-Oxo-2-(((S)-1-phenylethyl)amino)-1-(pyridin-3-yl)ethyl)-N(prop-2-yn-1-yl)benzamide (6n). Using the general procedure, this compound was obtained as a pale yellow solid in 74% yield (1.0 mmol scale) after purification by flash column chromatography (30% hexanes–EtOAc). Rf 0.25 (30% hexanes– EtOAc), mp: 58–60 °C. 1H NMR (400 MHz, CDCl3) δ ( ppm):


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8.54 (br s, 1H), 8.55–8.41 (m, 1H), 7.83 and 7.63 (br s, 1H), 7.47 (dd, J = 8.8 Hz, 2H), 7.41–7.12 (m, 9H), 7.00 (d, J = 7.8 Hz, 1H), 6.91 (d, J = 7.9 Hz, 1H), 5.95 (br s, 1H), 5.15–5.07 (m, 1H), 4.15 (dd, J = 18.5, 3.1 Hz, 1H), 3.96 (dd, J = 19.3, 4.5 Hz, 1H), [1.92 (t, J = 2.4 Hz) and 1.84 (s, 1H)], [1.44 (d, J = 7.0 Hz) and 1.41 (d, J = 6.9 Hz, 3H)]. 13C NMR (100 MHz, CDCl3) δ ( ppm): 172.6, 167.7, 151.2, 149.8, 149.7, 143.1, 142.9, 137.4, 137.2, 134.8, 130.8, 130.8, 128.8, 128.8, 128.7, 127.6, 127.5, 127.3, 127.2, 126.3, 126.2, 123.7, 123.6, 79.3, 79.2, 72.7, 60.3, 49.6, 49.5, 38.5, 22.0, 21.9. IR v (cm−1) 509, 537, 699, 709, 945, 1023, 1140, 1192, 1245, 1342, 1372, 1406, 1447, 1544, 1636, 2121, 2924, 2975, 3031, 3062, 3225, 3287. HRMS (FAB+, M+) calcd for C25H24N3O2: [M + 1] 398.1869, found: 398.1876. N-(2-(((S)-1-(Naphthalen-1-yl)ethyl)amino)-2-oxo-1-( pyridin3-yl)ethyl)-N-( prop-2-yn-1-yl)benzamide (6n′). Using the general procedure, this compound was obtained as a pale yellow solid in 55% yield (0.5 mmol scale) after purification by flash column chromatography (50% EtOAc–hexanes). Rf 0.30 (50% EtOAc–hexanes), mp: 83–85 °C. 1H NMR (400 MHz, CDCl3) δ ( ppm): 8.60 (br s, 1H), 8.53 (br s, 1H), 8.16 (d, J = 8.4 Hz, 1H), 8.11 (d, J = 8.2 Hz, 1H), 7.91–7.84 (m, 1H), 7.84–7.76 (m, 1H), 7.62–7.28 (m, 9H), 7.25–7.19 (m, 1H), 6.98–6.70 (m, 1H), 6.02 (m, 1H), 5.91 (s, 1H), 4.21 (ddd, J = 18.4, 4.6, 2.4 Hz, 1H), 4.07–3.89 (m, 1H), 2.02 (t, J = 2.5 Hz, 1H), (1.75 (d, J = 6.8 Hz) and 1.70 (d, J = 6.8 Hz), 3H). 13C NMR (100 MHz, CDCl3) δ ( ppm): 172.6, 167.4, 151.1, 150.8, 149.8, 149.6, 138.1, 137.7, 137.2, 134.6, 134.1, 131.1, 131.0, 130.9, 130.8, 129.0, 128.8, 128.6, 127.2, 126.8, 126.6, 126.1, 126.0, 125.4, 123.4, 123.3, 122.8, 79.2, 79.1, 73.0, 45.5, 21.0. IR v (cm−1): 442, 626, 665, 700, 777, 798, 1027, 1138, 1178, 1242, 1399, 1511, 1633, 3050, 3287. HRMS (EI+) calcd for C29H25N3O2: [M−] 447.1958, found: 447.1947. N-(2-(Naphthalen-2-ylamino)-2-oxo-1-( pyridin-3-yl)ethyl)-N( prop-2-yn-1-yl)benzamide (6o). Using the general procedure, this compound was obtained as an orange solid in 33% yield (1.0 mmol scale) after purification by flash column chromatography (EtOAc–hexanes 4 : 6). Rf 0.15 (40% EtOAc-hexanes), mp: 82–84 °C. 1H NMR (400 MHz, CDCl3) δ ( ppm): 9.40 (s, 1H), 8.71 (s, 1H), 8.61 (s, 1H), 8.23 (s, 1H), 7.98 (s, 1H), 7.77–7.60 (m, 5H), 7.54–7.29 (m, 7H), 6.31 (s, 1H), 4.37 (dd, J = 18.5, 2.5 Hz, 1H), 4.20 (d, J = 18.5 Hz, 1H), 2.05 (t, J = 4.5 Hz, 1H). 13C NMR (100 MHz, CDCl3) δ ( ppm): 173.2, 167.4, 151.2, 149.9, 137.3, 135.2, 134.5, 133.8, 131.1, 130.9, 130.4, 128.8, 128.8, 127.8, 127.6, 127.5, 126.6, 125.2, 123.9, 119.9, 117.0, 79.2, 73.1, 61.4, 39.0. IR v (cm−1): 472, 634, 697, 709, 744, 812, 856, 1141, 1190, 1234, 1254, 1362, 1394, 1433, 1504, 1556, 1588, 1622, 1691, 2162, 3055, 3285. HRMS (FAB+, M+) calcd for C27H22N3O2: [M + 1] 420.1712, found: 420.1714. N-(2-(tert-Butylamino)-2-oxo-1-( pyridin-3-yl)ethyl)-N-( prop-2yn-1-yl)nicotinamide (6p). Using the general procedure, this compound was obtained as a pale yellow solid in 74% yield (1.0 mmol scale) after purification by flash column chromatography (EtOAc). Rf 0.15 (EtOAc), mp: 150–152 °C. 1H NMR (400 MHz, CDCl3) δ ( ppm): 8.85 (s, 1H), 8.70 (ddd, J = 4.7, 1.8, 0.8 Hz, 1H), 8.65–8.57 (m, 2H), 7.94 (dd, J = 6.1, 1.9 Hz, 1H), 7.87 (d, J = 6.8 Hz, 1H), 7.36 (ddd, J = 9.3, 8.0, 4.9 Hz, 2H),


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6.28 (s, 1H), 5.97 (br s, 1H), 4.28 (dd, J = 18.8, 2.5 Hz, 1H), 4.07 (d, J = 18.4 Hz, 1H), 2.01 (t, J = 2.0 Hz, 1H), 1.39 (s, 9H). 13 C NMR (100 MHz, CDCl3) δ ( ppm): 170.1, 167.5, 151.5, 151.3, 149.9, 148.1, 137.3, 135.0, 131.1, 130.7, 123.8, 123.4, 79.1, 72.9, 60.3, 52.2, 38.0, 28.7. IR v (cm−1): 713, 944, 981, 1029, 1147, 1226, 1255, 1362, 1407, 1450, 1427, 1560, 1593, 1641, 1676, 2116, 2963, 3058, 3204. LRMS (FAB+): 351 (85) [M + 1], 307 (35), 289 (16), 278 (12), 250 (8), 154 (100), 136 (60). N-(2-(tert-Butylamino)-2-oxo-1-( pyridin-3-yl)ethyl)-N-( prop-2yn-1-yl)-2-naphthamide (6q). Using the general procedure, this compound was obtained as a pale yellow solid in 42% yield (1.0 mmol scale) after purification by flash column chromatography (50% EtOAc–hexanes). Rf 0.25 (50% EtOAc–hexanes), mp: 76–78 °C. 1H NMR (400 MHz, CDCl3) δ ( ppm): 8.81–8.67 (m, 1H), 8.62 (d, J = 4.4 Hz, 1H), 8.14 (s, 1H), 7.95–7.83 (m, 4H), 7.66 (dd, J = 8.3, 1.8 Hz, 1H), 7.59–7.51 (m, 2H), 7.35 (dd, J = 8.0, 4.8 Hz, 1H), 6.18 (br s, 1H), 5.92 (br s, 1H), 4.30 (dd, J = 18.5, 2.5 Hz, 1H), 4.15 (d, J = 17.7 Hz, 1H), 2.07 (t, J = 2.5 Hz, 1H), 1.42 (s, 9H). 13C NMR (100 MHz, CDCl3) δ ( ppm): 172.6, 167.8, 151.1, 149.7, 137.5, 134.3, 132.7, 132.1, 131.1, 128.7, 128.0 127.7, 127.0, 124.2, 123.8, 79.5, 72.8, 61.3, 52.2, 38.5, 28.8. IR v (cm−1): 478, 710, 758, 942, 1191, 1221, 1361, 1398, 1548, 1620, 1675, 2117, 2924, 2964, 3058, 3310. HRMS (FAB+, M+) calcd for C25H26N3O2: [M + 1] 400.2025, found: 400.2017. N-(2-(tert-Butylamino)-2-oxo-1-( pyridin-3-yl)ethyl)-N-( prop-2yn-1-yl)-[1,1′:4′,1″-terphenyl]-4-carboxamide (6r). Using the general procedure, this compound was obtained as a pale yellow solid in 29% yield (1.0 mmol scale) after purification by flash column chromatography (50% EtOAc–hexanes). Rf 0.70 (EtOAc), mp: 180–182 °C. 1H NMR (400 MHz, CDCl3) δ ( ppm): 8.69 (s, 1H), 8.61 (d, J = 4.6 Hz, 1H), 7.91 (s, 1H), 7.71 (br s, 4H), 7.69 (br s, 4H), 7.64 (dd, J = 7.3, 1.5 Hz, 2H), 7.46 (dd, J = 7.6, 1.7 Hz, 2H), 7.40–7.31 (m, 2H), 6.24 (s, 1H), 5.90 (br s, 1H), 4.31 (dd, J = 18.7, 2.3 Hz, 1H), 4.14 (dd, J = 18.4, 2.6 Hz, 1H), 2.07 (t, J = 2.1 Hz, 1H), 1.41 (s, 9H). 13C NMR (100 MHz, CDCl3) δ ( ppm): 172.3, 167.8, 151.3, 149.8, 143.2, 141.0, 140.5, 138.9, 137.3, 133.6, 131.0, 129.0, 128.0, 127.7, 127.6, 127.3, 127.2, 123.7, 79.5, 72.8, 61.1, 52.2, 38.5, 28.8. IR v (cm−1): 694, 757, 831, 1142, 1193, 1222, 1255, 1334, 1363, 1393, 1548, 1634, 1679, 2115, 2928, 2966, 3032, 3055, 3238. LRMS (FAB+): 502 [M + 1], 429 (15), 257 (100), 228 (12), 154 (12), 136 (11), 89 (7), 57 (6). 2-(Benzo[d][1,3]dioxol-5-yl)-N-(2-(tert-butylamino)-2-oxo-1( pyridin-3-yl)ethyl)-N-( prop-2-yn-1-yl)acetamide (6s). Using the general procedure, this compound was obtained as a white solid in 57% yield (1.0 mmol scale) after purification by flash column chromatography (50% EtOAc–hexane). Rf 0.25 (50% EtOAc–hexanes), mp: 130–132 °C. 1H NMR (400 MHz, CDCl3) δ ( ppm): 8.59 (s, 1H), 8.58 (s, 1H), 7.78 (d, J = 7.6 Hz, 1H), 7.33–7.26 (m, 1H), 6.75 (d, J = 6.4 Hz, 2H), 6.70 (d, J = 8.0 Hz, 1H), 6.15 (s, 1H), 6.02 (s, 1H), 5.94 (s, 2H), 4.12 (s, 2H), 3.85 (s, 2H), 2.12 (s, 1H), 1.34 (s, 9H). 13C NMR (100 MHz, CDCl3) δ ( ppm): 172.4, 167.7, 150.8, 149.6, 148.1, 146.9, 137.0, 131.0, 127.7, 123.5, 122.2, 109.5, 108.6, 101.2, 79.2, 72.7, 59.0, 52.1, 40.7, 35.6, 28.7. IR v (cm−1): 708, 783, 925, 1037, 1155, 1187, 1246, 1359, 1404, 1441, 1486, 1503, 1560, 1646, 2113, 2924,

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2971, 3087, 3211, 3313. HRMS (FAB+, M+) calcd for C23H26N3O4: [M + 1] 408.1923, found: 408.1926. tert-Butyl (4-((2-(tert-butylamino)-2-oxo-1-(pyridin-3-yl)ethyl)(prop-2-yn-1-yl)amino)-4-oxobutyl)carbamate (6t). Using the general procedure, this compound was obtained as a white solid in 46% yield (1.0 mmol scale) after purification by flash column chromatography (20% EtOAc–hexanes). Rf 0.20 (20% EtOAc–hexanes), mp: 172–174 °C. 1H NMR (400 MHz, CDCl3) δ ( ppm): 8.59 (d, J = 2.1 Hz, 1H), 8.58 (d, J = 1.6 Hz, 1H), 7.78 (d, J = 8.0 Hz, 1H), 7.31 (dd, J = 8.0, 4.8 Hz, 1H), 6.15 (s, 1H), 5.98 (br s, 1H), 4.81 (br s, 1H), 4.13 (s, 2H), 3.22–317 (m, 2H), 2.60 (dd, J = 7.2, 4.4 Hz, 2H), 2.05 (t, J = 2.6 Hz, 2H), 1.90 (t, J = 6.9 Hz, 1H), 1.44 (s, 9H), 1.37 (s, 9H). 13C NMR (100 MHz, CDCl3) δ ( ppm): 173.8, 167.9, 156.2, 150.8, 149.6, 137.2, 131.2, 123.6, 79.3, 79.1, 72.5, 59.0, 52.1, 40.0, 35.6, 30.8, 28.7, 28.5, 25.4. IR v (cm−1): 631, 663, 713, 1095, 1163, 1252, 1363, 1454, 1551, 1661, 1697, 2973, 3082, 3295. HRMS (FAB+, M+) calcd for C23H35N4O4: [M + 1] 431.2658, found: 431.2662. N-(2-(tert-Butylamino)-2-oxo-1-( pyridin-3-yl)ethyl)-N-( prop-2yn-1-yl)decanamide (6u). Using the general procedure, this compound was obtained as an orange solid in 37% yield (1.0 mmol scale) after purification by flash column chromatography (40% EtOAc–hexanes). Rf 0.30 (50% EtOAc–hexanes), mp: 82–84 °C. 1H NMR (400 MHz, CDCl3) δ ( ppm): 8.58 (s, 1H), 8.57 (s, 1H), 7.78 (d, J = 8.0 Hz, 1H), 7.31 (dd, J = 8.0, 4.9 Hz, 1H), 6.19 (s, 1H), 6.17 (s, 1H), 4.23–4.06 (m, 2H), 2.53 (t, J = 7.2 Hz, 2H), 2.04 (s, 1H), 1.65–1.72 (m, 2H), 1.37 (s, 9H), 1.34–1.22 (m, 12H), 0.92–0.80 (m, 3H). 13C NMR (100 MHz, CDCl3) δ ( ppm): 174.5, 168.1, 150.8, 149.5, 137.1, 131.3, 123.5, 79.3, 72.2, 58.5, 52.0, 35.5, 33.7, 32.0, 29.5, 29.5, 29.4, 28.7, 25.1, 22.8, 14.2. IR v (cm−1): 622, 657, 716, 1191, 1215, 1225, 1427, 1455, 1559, 1634, 1675, 2853, 2925, 2956, 3047, 3218, 3308. HRMS (FAB+, M+) calcd for C24H38N3O2: [M + 1] 400.2964, found: 400.2966. N-(2-(tert-Butylamino)-2-oxo-1-( pyridin-4-yl)ethyl)-N-( prop-2yn-1-yl)benzamide (6v). Using the general procedure, this compound was obtained as a red solid in 49% yield (1.0 mmol scale) after purification by flash column chromatography (50% EtOAc–hexanes). Rf 0.10 (50% EtOAc–hexanes), mp: 121–123 °C. 1H NMR (400 MHz, CDCl3) δ ( ppm): 8.62 (dd, J = 4.6, 1.7 Hz, 2H), 7.60 (d, J = 7.2 Hz, 2H), 7.51–7.36 (m, 5H), 6.41 (s, 1H), 5.75 (s, 1H), 4.28 (ddd, J = 18.3, 2.4, 1.1 Hz, 1H), 4.06 (ddd, J = 18.4, 2.4, 1.2 Hz, 1H), 2.13 (s, 1H), 1.40 (s, 9H). 13 C NMR (100 MHz, CDCl3) δ ( ppm): 172.6, 167.3, 150.2, 150.2, 144.1, 134.7, 130.9, 128.8, 127.2, 124.1, 79.2, 73.1, 63.1, 52.1, 39.2, 28.7. IR v (cm−1): 529, 566, 623, 695, 1140, 1190, 1223, 1255, 1363, 1401, 1425, 1558, 1602, 1638, 1678, 1975, 2962, 3036, 3208. HRMS (FAB+, M+) calcd for C21H24N3O2: [M + 1] 350.1947, found: 350.1950. N-(2-(tert-Butylamino)-2-oxo-1-( pyridin-2-yl)ethyl)-N-( prop-2yn-1-yl)benzamide (6w). Using the general procedure, this compound was obtained as an orange solid in 56% yield (1.0 mmol scale) after purification by flash column chromatography (40% EtOAc–hexanes). Rf 0.35 (50% EtOAc–hexanes), mp: 129–131 °C. 1H NMR (400 MHz, CDCl3) δ ( ppm): 8.65–8.48 (m, 1H), 7.76–7.54 (m, 5H), 7.46–7.38 (m, 3H),

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7.30–7.22 (m, 1H), 5.74 (br s, 1H), 4.30 (br s, 2H), 2.13–2.01 (m, 1H), 1.41 (s, 9H). 13C NMR (100 MHz, CDCl3) δ ( ppm): 172.4, 166.8, 155.9, 148.7, 137.3, 135.4, 130.4, 128.6, 127.3, 124.1, 123.0, 79.6, 72.3, 64.2, 51.8, 40.0, 28.8. IR v (cm−1): 570, 616, 653, 701, 788, 1178, 1221, 1400, 1438, 1448, 1551, 1618, 1677, 1980, 2967, 3297, 3315. HRMS (FAB+, M+) calcd for C21H24N3O2: [M + 1] 350.1869, found: 350.1871. N-(2-(tert-Butylamino)-2-oxo-1-(pyrimidin-5-yl)ethyl)-N-(prop2-yn-1-yl)benzamide (6x). Using the general procedure, this compound was obtained as an orange oil in 17% yield (1.0 mmol scale) after purification by flash column chromatography (50% EtOAc–hexanes). Rf 0.25 (50% EtOAc–hexanes). 1 H NMR (400 MHz, CDCl3) δ ( ppm): 9.23 (s, 1H), 8.93 (s, 2H), 8.10 (d, J = 7.7 Hz, 1H), 7.60 (d, J = 7.3 Hz, 2H), 7.54–7.42 (m, 3H), 6.37 (s, 1H), 5.88 (s, 1H), 4.31 (d, J = 18.5 Hz, 1H), 4.12 (d, J = 18.6 Hz, 1H), 2.17 (s, 1H), 1.41 (s, 9H). 13C NMR (100 MHz, CDCl3) δ ( ppm): 172.7, 166.8, 158.4, 158.1, 134.3, 133.4, 131.2, 130.2, 129.3, 128.9, 128.5, 127.3, 79.1, 73.8, 59.6, 52.3, 38.8, 28.8. IR v (cm−1): 631, 644, 699, 715, 787, 914, 1220, 1256, 1364, 1407, 1448, 1549, 1626, 1680, 2118, 2503, 2969, 3062, 3300. HRMS (FAB+, M+) calcd for C20H23N4O2: [M + 1] 351.1821, found: 351.1822. General procedure for the synthesis of nicotine analogs 8a–x To a solution of the corresponding Ugi adduct 6a–x (1.0 equiv.) in anhydrous THF (0.1 M) was added potassium tert-butoxide at once (2.5 equiv.). The resulting mixture was stirred at room temperature under a nitrogen atmosphere until completion was indicated by TLC (1.0 h). The reaction mixture was concentrated under reduced pressure, the residue was taken up in MeOH (0.1 M), and then 20% Pd(OH)2 (20 wt%) was added and the solution was stirred at room temperature under a hydrogen atmosphere (balloon) until completion was indicated by TLC (5.0 h). The reaction mixture was concentrated under reduced pressure, the crude was dissolved in CH2Cl2 (20 mL), and then filtered over a short pad of Celite. The filtrate was washed with water (20 mL), the aqueous layer was extracted back with CH2Cl2 (2 × 20 mL), and then the organic extracts were combined, dried (Na2SO4) and concentrated in vacuo to give the corresponding nicotine analogs 8a–x. Any modification to this protocol is indicated. N-(tert-Butyl)-1-(4-methoxybenzoyl)-2-(pyridin-3-yl)-2,3-dihydro1H-pyrrole-2-carboxamide (7b). Using only the first step of the general procedure, this compound was obtained from the Ugi adduct 6b (0.0911 g, 0.24 mmol) as a white solid (0.0405 g, 0.11 mmol) in 44% yield after purification by column chromatography (50% EtOAc–hexane). Rf 0.51 (EtOAc), mp: 117–119 °C. 1H NMR (400 MHz, CDCl3) δ ( ppm): 8.63 (dd, J = 2.4, 1.2 Hz, 1H), 8.51 (ddd, J = 4.8, 1.5, 0.8 Hz, 1H), 8.40 (br s, 1H), 7.64 (dddd, J = 8.1, 2.5, 1.7, 0.9 Hz, 1H), 7.59 (d, J = 8.0 Hz, 2H), 7.29–7.24 (m, 1H), 6.96 (d, J = 8.0 Hz, 2H), 6.55 (dddd, J = 4.5, 2.7, 1.7, 0.8 Hz, 1H), 5.26 (dddd, J = 4.3, 3.2, 2.2, 0.9 Hz, 1H), 4.16 (dddd, J = 17.0, 3.0, 1.7, 0.8 Hz, 1H), 3.87 (s, 3H), 2.68 (dddd, J = 17.1, 2.5, 1.7, 0.9 Hz, 1H), 1.39 (s, 9H). 13 C NMR (100 MHz, CDCl3) δ ( ppm): 169.1, 168.3, 162.2, 148.6, 147.0, 137.0, 133.0, 130.9, 130.4, 127.4, 123.3, 114.0, 110.1,


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75.9, 55.6, 51.6, 44.7, 28.6. IR v (cm−1): 696, 716, 844, 1009, 1019, 1163, 1183, 1222, 1253, 1363, 1380, 1554, 1604, 1674, 2924, 2963, 3254. HRMS (FAB+, M+) calcd for C22H26N3O3: [M + 1] 380.1974, found: 380.1967. N-(tert-Butyl)-1-(4-methoxybenzoyl)-2-(pyridin-3-yl)-2,5-dihydro1H-pyrrole-2-carboxamide (7b′). Using only the first step of the general procedure, this compound was obtained from the Ugi adduct 6b (0.0911 g, 0.24 mmol) as a white solid (0.0332 g, 0.09 mmol, 36%) after purification by column chromatography (50% EtOAc–hexanes), Rf 0.30 (EtOAc), mp: 120–122 °C. 1 H NMR (400 MHz, CDCl3) δ ( ppm): 8.54 (s, 1H), 8.52 (s, 1H), 8.02 (br s, 1H), 7.65 (d, J = 8.0 Hz, 1H), 7.42 (d, J = 8.4 Hz, 2H), 7.30 (dd, J = 7.8, 4.8 Hz, 1H), 6.94 (d, J = 8.5 Hz, 2H), 6.01 (d, J = 6.4 Hz, 1H), 5.86 (d, J = 6.3 Hz, 1H), 4.57 (d, J = 15.1 Hz, 1H), 4.42 (d, J = 14.9 Hz, 1H), 3.85 (s, 3H), 1.40 (s, 9H). 13C NMR (100 MHz, CDCl3) δ ( ppm): 170.8, 169.6, 161.2, 148.6, 147.5, 135.6, 134.0, 133.7, 128.8, 128.2, 123.3, 122.8, 114.0, 80.2, 58.5, 55.5, 51.7, 28.7. IR v (cm−1): 703, 850, 1023, 1177, 1223, 1263, 1364, 1388, 1554, 1599, 1667, 2865, 2959, 2924, 3246. HRMS (FAB+, M+) calcd for C22H26N3O3: [M + 1] 380.1974, found: 380.1980. 1-Benzoyl-N-(tert-butyl)-2-( pyridin-3-yl)pyrrolidine-2-carboxamide (8a). According to general procedure B, this compound was obtained from the Ugi adduct 6a (0.472 g, 1.35 mmol) as a white solid (0.400 g, 1.14 mmol in 84% yield. Rf 0.48 (EtOAc), mp: 134–136 °C. 1H NMR (300 MHz, CDCl3) δ ( ppm): 8.57 (dd, J = 2.5, 0.9 Hz, 1H), 8.51 (dd, J = 4.8, 1.6 Hz, 1H), 8.18 (s, 1H), 7.58 (ddd, J = 8.0, 2.5, 1.6 Hz, 1H), 7.52–7.44 (m, 5H), 7.30–7.26 (m, 1H), 3.79–3.60 (m, 2H), 3.30–3.21 (m, 1H), 2.02–1.75 (m, 3H), 1.38 (s, 9H). 13C NMR (75 MHz, CDCl3) δ ( ppm): 171.2, 169.8, 148.4, 147.0, 137.2, 136.8, 133.0, 130.4, 128.8, 126.4, 123.2, 74.8, 53.2, 51.5, 41.5, 28.7, 24.1. IR v (cm−1): 658, 702, 714, 723, 747, 811, 1023, 1114, 1232, 1288, 1362, 1421, 1447, 1555, 1598, 1668, 2924, 2959, 3065, 3241. HRMS (FAB+, M+) calcd for C21H26N3O2: [M + 1] 352.2025, found: 352.2025. N-(tert-Butyl)-1-(4-methoxybenzoyl)-2-(pyridin-3-yl)pyrrolidine2-carboxamide (8b). According to the general procedure, this compound was obtained from the Ugi adduct 6b (0.040 g, 0.10 mmol) as a white solid in 75% yield (0.030 g, 0.079 mmol). Rf 0.50 (EtOAc), mp: 144–146 °C. 1H NMR (300 MHz, CDCl3) δ ( ppm): 8.55 (d, J = 2.5 Hz, 1H), 8.50 (dd, J = 4.8, 1.6 Hz, 1H), 8.27 (s, 1H), 7.57 (ddd, J = 8.0, 2.5, 1.6 Hz, 1H), 7.51 (d, J = 8.9 Hz, 2H), 7.31–7.23 (m, 1H), 6.95 (d, J = 8.8 Hz, 2H), 3.85 (s, 3H), 3.87–3.79 (m, 1H), 3.73–3.66 (m, 1H), 3.28–3.21 (m, 1H), 2.05–1.75 (m, 3H), 1.37 (s, 9H). 13C NMR (75 MHz, CDCl3) δ ( ppm): 170.9, 169.9, 161.3, 148.3, 147.0, 136.9, 133.0, 129.3, 128.7, 123.2, 113.9, 74.8, 55.5, 53.3, 51.4, 41.4, 28.7, 24.1. IR v (cm−1): 715, 775, 840, 1023, 1112, 1178, 1252, 1362, 1402, 1419, 1514, 1556, 1599, 1667, 2961, 3059, 3243. HRMS (FAB+, M+) calcd for C22H28N3O3: [M + 1] 382.2131, found: 382.2137. N-(tert-Butyl)-1-(3,4-dimethoxybenzoyl)-2-( pyridin-3-yl)pyrrolidine-2-carboxamide (8c). According to the general procedure, this compound was obtained from the Ugi adduct 6c (0.082 g, 0.2 mmol) as a yellow pale solid in 80% yield (0.066 g,


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0.16 mmol). Rf 0.48 (EtOAc), mp: 141–143 °C. 1H NMR (300 MHz, CDCl3) δ ( ppm): 8.55 (br s, 1H), 8.50 (d, J = 6.0 Hz, 1H), 8.11 (br s, 1H), 7.58 (ddd, J = 8.1, 2.5, 1.6 Hz, 1H), 7.30–7.26 (m, 1H), 7.16 (dd, J = 8.2, 2.0 Hz, 1H), 7.04 (d, J = 2.0 Hz, 1H), 6.90 (d, J = 8.3 Hz, 1H), 3.93 (s, 3H), 3.93 (s, 3H), 3.88–3.68 (m, 2H), 3.29–3.21 (m, 1H), 2.02–1.78 (m, 3H), 1.37 (s, 9H). 13C NMR (75 MHz, CDCl3) δ ( ppm): 170.8, 169.9, 151.0, 149.1, 148.4, 147.1, 133.1, 129.4, 123.2, 120.0, 110.6, 110.4, 74.8, 56.2, 56.2, 53.4, 51.5, 41.3, 28.7, 24.0. IR v (cm−1) 712, 753, 778, 864, 1025, 1140, 1227, 1241, 1262, 1396, 1423, 1453, 1518, 1562, 1604, 1667, 2927, 2958, 3065, 3222, 3594. HRMS (FAB+, M+) calcd for C23H30N3O4: [M + 1] 412.2236, found: 412.2240. N-(tert-Butyl)-1-(4-(dimethylamino)benzoyl)-2-( pyridin-3-yl)pyrrolidine-2-carboxamide (8d). According to the general procedure, this compound was obtained from the Ugi adduct 6d (0.039 g, 0.1 mmol) as a pale yellow solid in 75% yield (0.0293 g, 0.075 mmol). In the reduction step, the reaction was stirred for 19 h under the same conditions. Rf 0.25 (20% EtOAc–hexanes), mp: 148–150 °C. 1H NMR (300 MHz, CDCl3) δ ( ppm): 8.55–8.52 (m, 2H), 8.53 (br s, 1H), 8.47 (d, J = 5.0 Hz, 1H), 7.56 (ddd, J = 8.1, 2.5, 1.6 Hz, 1H), 7.50 (d, J = 9.0 Hz, 2H), 7.27–7.22 (m, 1H), 6.68 (d, J = 9.0 Hz, 2H), 3.99–3.90 (m, 1H), 3.80–3.73 (m, 1H), 3.26–3.20 (m, 1H), 3.02 (s, 6H), 1.99–1.73 (m, 3H), 1.36 (s, 9H). 13C NMR (75 MHz, CDCl3) δ ( ppm): 171.3, 170.2, 151.9, 148.1, 147.0, 137.3, 133.0, 129.0, 123.7, 123.1, 111.1, 74.9, 53.2, 51.3, 41.4, 40.2, 28.6, 24.1. IR v (cm−1): 711, 770, 824, 941, 1173, 1200, 1227, 1363, 1402, 1416, 1528, 1548, 1589, 1607, 1667, 2925, 2953, 3054, 3217. HRMS (FAB+, M+) calcd for C23H31N4O2: [M + 1] 395.2447, found: 395.2449. N-(tert-Butyl)-1-(2-methylbenzoyl)-2-( pyridin-3-yl)pyrrolidine2-carboxamide (8e). According to the general procedure, this compound was obtained from the Ugi adduct 6e (0.036 g, 0.1 mmol) as a pale yellow solid in 75% yield (0.027 g, 0.075 mmol). Rf 0.27 (50% EtOAc–hexane), mp: 158–160 °C. 1 H NMR (300 MHz, CDCl3) δ ( ppm): 8.60 (d, J = 3.0 Hz, 1H), 8.53 (dd, J = 4.9, 1.6 Hz, 1H), 8.22 (br s, 1H), 7.60 (ddd, J = 8.0, 2.5, 1.6 Hz, 1H), 7.33–7.23 (m, 5H), 3.54–3.36 (m, 2H), 3.21–3.28 (m, 1H), 2.38 (s, 3H), 2.04–1.72 (m, 3H), 1.39 (s, 9H). 13 C NMR (75 MHz, CDCl3) δ ( ppm): 171.5, 169.7, 148.4, 146.9, 137.2, 136.9, 133.6, 132.9, 130.9, 129.4, 126.3, 124.9, 123.3, 74.3, 52.5, 51.5, 41.7, 28.7, 24.2, 19.1. IR v (cm−1): 654, 709, 748, 796, 1024, 1110, 1228, 1359, 1415, 1554, 1595, 1609, 1672, 2926, 2960, 3057, 3241. HRMS (FAB+, M+) calcd for C22H28N3O2: [M + 1] 366.2182, found: 366.2184. N-(tert-Butyl)-1-(4-ethylbenzoyl)-2-(pyridin-3-yl)pyrrolidine-2carboxamide (8f). According to the general procedure, this compound was obtained from the Ugi adduct 6f (0.038 g, 0.1 mmol) as a pale yellow solid in 76% yield (0.029 g, 0.076 mmol). Rf 0.29 (50% EtOAc–hexanes), mp: 131–133 °C. 1 H NMR (300 MHz, CDCl3) δ ( ppm): 8.56 (dd, J = 2.6, 0.8 Hz, 1H), 8.50 (dd, J = 4.8, 1.6 Hz, 1H), 8.25 (br s, 1H), 7.57 (ddd, J = 8.0, 2.5, 1.6 Hz, 1H), 7.44 (d, J = 8.3 Hz, 2H), 7.29–7.25 (m, 3H), 3.83–3.74 (m, 1H), 3.68–3.62 (m, 1H), 3.29–3.21 (m, 1H), 2.69 (q, J = 7.6 Hz, 2H), 2.02–1.75 (m, 3H), 1.37 (s, 9H), 1.25 (t,

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J = 7.6 Hz, 3H). 13C NMR (75 MHz, CDCl3) δ ( ppm): 171.4, 169.9, 148.3, 147.0, 146.9, 136.9, 134.4, 133.0, 128.1, 126.7, 123.2, 74.7, 53.2, 51.4, 41.4, 28.9, 28.7, 24.1, 15.5. IR v (cm−1): 710, 840, 1112, 1226, 1287, 1362, 1403, 1415, 547, 1600, 1669, 2932, 2967, 3051, 3244. HRMS (FAB+, M+) calcd for C23H30N3O2: [M + 1] 380.2338, found: 380.2333. N-(tert-Butyl)-1-(2-chlorobenzoyl)-2-( pyridin-3-yl)pyrrolidine2-carboxamide (8g). According to the general procedure, this compound was obtained from the Ugi adduct 8g (0.076 g, 0.2 mmol) as a white solid in 82% yield (0.063 g, 0.163 mmol). Rf 0.42 (EtOAc), mp: 124–126 °C. 1H NMR (300 MHz, CDCl3) δ ( ppm): 8.57 (d, J = 3.0 Hz, 1H), 8.51 (d, J = 3.0 Hz, 1H), 8.18 (br s, 1H), 7.58 (ddd, J = 8.1, 2.5, 1.6 Hz, 1H), 7.54–7.42 (m, 5H), 7.33–7.24 (m, 1H), 3.82–3.57 (m, 2H), 3.34–3.18 (m, 1H), 2.10–1.73 (m, 3H), 1.38 (s, 9H). 13C NMR (75 MHz, CDCl3) δ ( ppm): 171.2, 169.8, 148.4, 147.0, 137.1, 136.8, 133.0, 130.4, 128.8, 126.4, 123.2, 74.7, 53.2, 51.5, 41.5, 28.7, 24.1. IR v (cm−1): 658, 701, 714, 747, 810, 1023, 1080, 1231, 1361, 1420, 1553, 1598, 1669, 2932, 2960, 3063, 3243. HRMS (FAB+, M+) calcd for C21H25ClN3O2: [M + 1] 386.1635, found: 386.1632. N-(tert-Butyl)-1-(2-fluorobenzoyl)-2-( pyridin-3-yl)pyrrolidine2-carboxamide (8h). Using the general procedure, this compound was obtained from the Ugi adduct 6h (0.036 g, 0.1 mmol) as a pale yellow solid in 74% yield (0.027 g, 0.074 mmol). Rf 0.32 (30% EtOAc–hexanes), mp: 98–100 °C. 1 H NMR (300 MHz, CDCl3) δ ( ppm): 8.58 (s, 1H), 8.52 (d, J = 4.8 Hz, 1H), 8.01 (s, 1H), 7.64 (ddd, J = 8.1, 2.5, 1.5 Hz, 1H), 7.45 (dddd, J = 8.3, 7.3, 5.5, 1.9 Hz, 1H), 7.39–7.34 (m, 1H), 7.32–7.28 (m, 1H), 7.28–7.22 (m, 1H), 7.20–7.14 (m, 1H), 3.73–3.62 (m, 1H), 3.60–3.51 (m, 1H), 3.28–3.16 (m, 1H), 2.16–1.70 (m, 3H), 1.39 (s, 9H). 13C NMR (75 MHz, CDCl3) δ ( ppm): 169.5, 167.0, 159.3, 156.8, 148.4, 147.2, 136.4, 133.2, 131.9, 131.8, 128.1, 128.1, 125.7, 125.5, 125.1, 125.0, 123.3, 116.4, 116.2, 74.9, 51.6, 51.4, 51.4, 41.8, 28.7, 24.0. IR v (cm−1): 646, 709, 752, 1024, 1102, 1209, 1228, 1288, 1359, 1418, 1455, 1552, 1606, 1671, 2927, 2960, 3065, 3259. HRMS (FAB+, M+) calcd for C21H25FN3O2: [M + 1] 370.1931, found: 370.1938. N-(tert-Butyl)-2-( pyridin-3-yl)-1-(4-(trifluoromethyl)benzoyl)pyrrolidine-2-carboxamide (8i). Using the general procedure, this compound was obtained from the Ugi adduct 6i (0.0417 g, 0.1 mmol) as a pale yellow solid in 72% yield (0.030 g, 0.072 mmol). Rf 0.20 (50% EtOAc–hexanes) mp: 102–104 °C. 1 H NMR (300 MHz, CDCl3) δ ( ppm): 8.57 (d, J = 2.5 Hz, 1H), 8.54 (dd, J = 4.8, 1.5 Hz, 1H), 7.86 (br s, 1H), 7.74 (d, J = 8.3 Hz, 2H), 7.62 (d, J = 8.1 Hz, 2H), 7.61–7.56 (m, 1H), 3.73 (m, 2H), 3.29–3.21 (m, 1H), 2.07–1.80 (m, 3H), 1.37 (s, 9H). 13C NMR (75 MHz, CDCl3) δ ( ppm): 169.8, 169.5, 148.6, 147.0, 140.4, 136.3, 133.1, 126.8, 126.0, 125.9, 123.3, 121.9, 74.9, 53.1, 51.7, 41.4, 28.7, 24.2. IR v (cm−1) 713, 858, 1017, 1064, 1112, 1126, 1166, 1227, 1324, 1361, 1422, 1553, 1603, 1671, 2924, 2960, 3062, 3255. HRMS (FAB+, M+) calcd for C22H25F3N3O2: [M + 1] 420.1899, found: 420.1895. 1-Benzoyl-N-(tert-butyl)-2-(6-methoxypyridin-3-yl)pyrrolidine2-carboxamide (8j). According to the general procedure, this

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compound was obtained from the Ugi adduct 6j (0.038 g, 0.1 mmol) as a pale yellow solid in 84% yield (0.032 g, 0.084 mmol). Rf 0.41 (60% EtOAc–hexanes), mp: 108–110 °C. 1 H NMR (300 MHz, CDCl3) δ ( ppm): 8.10 (dd, J = 2.7, 0.8 Hz, 1H), 8.08 (br s, 1H), 7.52–7.41 (m, 6H), 6.74 (dd, J = 8.7, 0.7 Hz, 1H), 3.94 (s, 3H), 3.72–3.52 (m, 2H), 3.22–3.15 (m, 1H), 1.98–1.75 (m, 3H), 1.37 (s, 9H). 13C NMR (75 MHz, CDCl3) δ ( ppm): 171.1, 170.2, 163.4, 143.9, 137.4, 136.2, 130.2, 129.4, 128.7, 126.4, 110.7, 74.4, 53.6, 53.1, 51.4, 41.4, 28.7, 24.0. IR v (cm−1): 561, 627, 657, 704, 722, 827, 1031, 1112, 1225, 1280, 1360, 1384, 1408, 1489, 1546, 1562, 1604, 1670, 2928, 2959, 3063, 3245. HRMS (FAB+, M+) calcd for C22H28N3O3: [M + 1] 382.2131, found: 382.2134. 1-Benzoyl-N-(tert-butyl)-2-(5-( p-tolyl)pyridin-3-yl)pyrrolidine2-carboxamide (8k). Using the general procedure, this compound was obtained from the Ugi adduct 6k (0.044 g, 0.1 mmol) as a pale yellow solid in 71% yield (0.0314 g, 0.071 mmol). Rf 0.42 (50% EtOAc–hexanes), mp: 154–156 °C. 1 H NMR (300 MHz, CDCl3) δ ( ppm): 8.72 (d, J = 2.1 Hz, 1H), 8.52 (d, J = 2.3 Hz, 1H), 8.28 (br s, 1H), 7.73 (m, 1H), 7.54–7.43 (m, 7H), 7.32–7.27 (m, 2H), 3.78 (m, 2H), 3.32–3.25 (m, 1H), 2.41 (s, 3H), 2.03–1.83 (m, 3H), 1.39 (s, 9H). 13C NMR (75 MHz, CDCl3) δ ( ppm): 171.3, 169.8, 146.8, 145.3, 138.2, 137.2, 136.7, 136.2, 134.9, 131.3, 130.3, 129.9, 128.8, 127.1, 126.4, 74.8, 53.3, 51.5, 41.5, 28.7, 24.1, 21.3. IR v (cm−1): 657, 696, 808, 1023, 1229, 1361, 1417, 1548, 1599, 1609, 1669, 2923, 2960, 3048, 3266. HRMS (FAB+, M+) calcd for C28H32N3O2: [M + 1] 442.2495, found: 442.2505. 1-Benzoyl-N-cyclohexyl-2-( pyridin-3-yl)pyrrolidine-2-carboxamide (8m). Using the general procedure, this compound was obtained from the Ugi adduct 6m (0.075 g, 0.2 mmol) as a pale yellow oil in 68% yield (0.051 g, 0.1351 mmol). For the cycloisomerization reaction, it was necessary to use 5.0 equiv. of potassium tert-butoxide (0.112 g, 0.1 mmol) and 22 h of reaction. Rf 0.30 (30% hexanes–EtOAc), 1H NMR (300 MHz, CDCl3) δ ( ppm): 8.57 (dd, J = 2.5, 0.9 Hz, 1H), 8.51 (dd, J = 4.8, 1.6 Hz, 1H), 8.20 (d, J = 7.5 Hz, 1H), 7.58 (ddd, J = 8.1, 2.5, 1.6 Hz, 1H), 7.54–7.40 (m, 5H), 7.34–7.25 (m, 1H), 3.92–3.60 (m, 3H), 3.31–3.23 (m, 1H), 2.07–1.76 (m, 6H), 1.73–1.51 (m, 4H), 1.45–1.13 (m, 7H). 13C NMR (75 MHz, CDCl3) δ ( ppm): 171.2, 169.9, 148.4, 146.9, 137.0, 136.6, 133.0, 130.3, 128.7, 126.3, 123.2, 74.1, 53.1, 48.7, 41.5, 32.6, 32.3, 25.6, 24.6, 24.5, 24.2. IR v (cm−1): 659, 699, 750, 1025, 1398, 1446, 1541, 1619, 1660, 2853, 2928, 3057, 3251. HRMS (FAB+, M+) calcd for C23H28N3O2: [M + 1] 378.2182, found: 378.2182. 1-Benzoyl-N-((S)-1-phenylethyl)-2-( pyridin-3-yl)pyrrolidine2-carboxamide (8n). Using the general procedure, this compound was obtained from the Ugi adduct 6n (0.079 g, 0.2 mmol) as a pale yellow oil in 50% yield after purification by flash column chromatography (30% hexanes–EtOAc) (0.039 g, 0.10 mmol). Rf 0.20 (30% hexanes–EtOAc). 1H NMR (400 MHz, CDCl3) δ ( ppm): 8.88 (d, J = 8.0 Hz, 1H), 8.74 (d, J = 7.7 Hz, 1H), 8.61 (d, J = 2.3 Hz, 1H), 8.54 (dd, J = 4.8, 1.5 Hz, 1H), 8.49 (dd, J = 4.8, 1.5 Hz, 1H), 8.45 (d, J = 2.5 Hz, 1H), 7.62 (ddd, J = 8.0, 2.5, 1.5 Hz, 1H), 7.57–7.51 (m, 2H), 7.51–7.38 (m, 8H), 7.36–7.21 (m, 12H), 7.19–7.13 (m, 1H), 5.25–5.14 (m, 1H),


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5.14–5.05 (m, 1H), 3.73 (ddd, J = 13.4, 10.5, 6.5 Hz, 3H), 3.61–3.48 (m, 1H), 3.35–3.15 (m, 2H), 2.04–1.72 (m, 8H), 1.48 (d, J = 6.7 Hz, 3H), 1.45 (d, J = 6.7 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ ( ppm): 171.6, 171.5, 170.1, 169.9, 148.4, 148.4, 146.8, 137.0, 137.0, 136.6, 136.3, 133.3, 132.9, 130.5, 130.4, 128.8, 128.8, 128.7, 128.7, 127.3, 127.2, 126.5, 126.4, 126.3, 126.0, 123.3, 123.2, 74.3, 74.2, 53.3, 53.3, 50.1, 49.9, 41.6, 41.5, 24.2, 24.2, 22.8, 22.8. IR v (cm−1): 658, 697, 1024, 1399, 1446, 1534, 1618, 1667, 2851, 2922, 2966, 3030, 3239. HRMS (FAB+, M+) calcd for C25H26N3O2: [M + 1] 400.2025, found: 400.2033. 1-Benzoyl-N-((S)-1-(naphthalen-1-yl)ethyl)-2-( pyridin-3-yl)pyrrolidine-2-carboxamide (8n′). Using the general procedure, this compound was obtained from the Ugi adduct 6n′ (0.045 g, 0.1 mmol) as a pale yellow oil in 41% yield after purification by flash column chromatography (10% hexanes–EtOAc) (0.018 g, 0.040 mmol). Rf 0.28 (10% hexanes–EtOAc). 1H NMR (400 MHz, CDCl3) δ ( ppm): 8.94 (d, J = 8.2 Hz, 1H), 8.76 (d, J = 7.8 Hz, 1H), 8.61 (s, 1H), 8.53 (d, J = 4.6 Hz, 1H), 8.50–8.41 (m, 2H), 8.21 (d, J = 8.5 Hz, 1H), 8.13–8.06 (m, 1H), 7.93–7.84 (m, 2H), 7.80–7.74 (m, 2H), 7.63–7.26 (m, 23H), 7.07 (dd, J = 8.1, 4.7 Hz, 1H), 6.92–6.86 (m, 2H), 5.99 (m, 2H), 3.83–3.62 (m, 3H), 3.42–3.21 (m, 3H), 2.12–1.95 (m, 2H), 1.94–1.73 (m, 4H), 1.70 (d, J = 6.8 Hz, 3H), 1.61 (d, J = 6.9 Hz, 3H).13C NMR (100 MHz, CDCl3) δ ( ppm): 171.6, 171.4, 170.0, 169.9, 148.5, 146.9, 146.8, 139.3, 139.0, 137.1, 136.8, 136.4, 136.1, 134.1, 134.1, 133.4, 132.7, 131.1, 130.9, 130.5, 130.1, 129.0, 129.0, 128.8, 128.6, 128.1, 128.0, 126.5, 126.3, 126.2, 126.0, 125.8, 125.6, 125.5, 123.3, 123.3, 123.1, 122.9, 122.8, 77.4, 74.3, 74.2, 53.3, 53.0, 46.0, 45.6, 41.7, 41.6, 29.9, 24.3, 24.2, 22.2, 20.9. IR v (cm−1): 658, 699, 777, 800, 1397, 1532, 1616, 1662, 2921, 3048, 3228. HRMS (EI+) calcd for C29H27N3O2: [M−] 449.2103, found: 449.2115. N-(tert-Butyl)-1-nicotinoyl-2-( pyridin-3-yl)pyrrolidine-2-carboxamide (8p). Using the general procedure, this compound was obtained from the Ugi adduct 6p (0.070 g, 0.2 mmol) as a pale yellow solid in 71% yield (0.050 g, 0.14 mmol) after purification by column chromatography (EtOAc). Rf 0.10 (EtOAc), mp: 121–123 °C. 1H NMR (300 MHz, CDCl3) δ ( ppm): 8.85–8.78 (m, 1H), 8.72 (dd, J = 4.9, 1.6 Hz, 1H), 8.57 (d, J = 2.5 Hz, 1H), 8.54 (dd, J = 4.8, 1.5 Hz, 1H), 7.89–7.82 (m, 1H), 7.85 (br s, 1H), 7.59 (dddd, J = 8.0, 2.4, 1.6, 0.7 Hz, 1H), 7.42 (ddd, J = 7.8, 4.9, 1.0 Hz, 1H), 7.31 (ddd, J = 8.0, 4.8, 0.7 Hz, 1H), 3.82–3.66 (m, 2H), 3.30–3.22 (m, 1H), 2.11–1.81 (m, 3H), 1.37 (s, 9H). 13C NMR (75 MHz, CDCl3) δ: ( ppm) 169.4, 168.7, 151.4, 148.6, 147.5, 147.0, 136.2, 134.4, 133.1, 132.9, 123.6, 123.3, 75.0, 53.1, 51.6, 41.4, 28.6, 24.2. IR v (cm−1): 680, 710, 1025, 1230, 1362, 1413, 1426, 1554, 1601, 1672, 2961, 3066, 3254. HRMS (FAB+, M+) calcd for C20H25N4O2: [M + 1] 353.1978, found: 353.1982. 1-(2-Naphthoyl)-N-(tert-butyl)-2-(pyridin-3-yl)pyrrolidine-2-carboxamide (8q). Using the general procedure, this compound was obtained from the Ugi adduct 6q (0.040 g, 0.1 mmol) as a pale yellow solid in 77% yield (0.0306 g, 0.076 mmol), Rf 0.15 (50% EtOAc–hexanes), mp: 70–72 °C. 1H NMR (400 MHz, CDCl3) δ ( ppm): 8.64–8.60 (m, 1H), 8.52 (dd, J = 4.8, 1.7 Hz, 1H), 8.19 (br s, 1H), 7.99 (br s, 1H), 7.95–7.85 (m, 3H), 7.64


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(ddd, J = 8.0, 2.5, 1.5 Hz, 1H), 7.60–7.53 (m, 3H), 7.35–7.28 (m, 1H), 3.86–3.75 (m, 1H), 3.74–3.66 (m, 1H), 3.34–3.21 (m, 1H), 2.10–1.77 (m, 3H), 1.40 (s, 9H). 13C NMR (100 MHz, CDCl3) δ ( ppm): 171.3, 169.8, 148.4, 147.1, 136.8, 134.4, 134.0, 133.1, 132.8, 128.8, 128.6, 128.0, 127.6, 127.1, 126.3, 123.5, 123.3, 74.9, 53.3, 51.6, 41.5, 28.7, 24.2. IR v (cm−1): 477, 710, 755, 780, 802, 1024, 1099, 1224, 1259, 1363, 1400, 1550, 1613, 1669, 2923, 2962, 3057, 3259. HRMS (FAB+, M+) calcd for C25H28N3O2: [M + 1] 402.2182, found: 402.2181. 1-([1,1′:4′,1″-Terphenyl]-4-carbonyl)-N-(tert-butyl)-2-( pyridin3-yl)pyrrolidine-2-carboxamide (8r). Using the general procedure, this compound was obtained from the Ugi adduct 6r (0.050 g, 0.1 mmol) as a pale yellow solid in 61% yield (0.0308 g, 0.061 mmol). In the reduction step, it was necessary to use 3 mL of MeOH. Rf 0.37 (30% EtOAc–hexanes), mp: 181–183 °C. 1H NMR (300 MHz, CDCl3) δ ( ppm): 8.59 (dd, J = 2.5, 0.8 Hz, 1H), 8.52 (dd, J = 4.8, 1.6 Hz, 1H), 8.20 (br s, 1H), 7.77–7.57 (m, 11H), 7.52–7.43 (m, 2H), 7.42–7.35 (m, 1H), 7.30 (ddd, J = 8.1, 4.8, 0.8 Hz, 1H), 3.91–3.67 (m, 2H), 3.35–3.20 (m, 1H), 2.09–1.77 (m, 3H), 1.39 (s, 9H). 13C NMR (75 MHz, CDCl3) δ ( ppm): 171.0, 169.8, 148.4, 147.0, 142.8, 141.0, 140.6, 139.0, 136.8, 135.8, 133.0, 129.0, 127.8, 127.7, 127.3, 127.2, 123.3, 74.8, 53.3, 51.5, 41.5, 28.7, 24.2. IR v (cm−1): 697, 711, 804, 828, 1005, 1023, 1109, 1224, 1364, 1392, 1547, 1608, 1669, 2923, 2962, 3031, 3252. HRMS (FAB+, M+) calcd for C33H34N3O2: [M + 1] 504.2651, found: 504.2651. 1-(2-(Benzo[d][1,3]dioxol-5-yl)acetyl)-N-(tert-butyl)-2-( pyridin3-yl)pyrrolidine-2-carboxamide (8s). According to the general procedure, this compound was obtained from the Ugi adduct 6s (0.041 g, 0.1 mmol) as a pale yellow solid in 78% yield (0.032 g, 0.078 mmol). In this case, it was necessary to use 1.0 equiv. of potassium tert-butoxide (0.011 g, 0.10 mmol). The reduction step was completed in 12 hours. Rf 0.25 (EtOAc), mp: 150–152 °C. 1H NMR (400 MHz, CDCl3) δ ( ppm): 8.46 (dd, J = 4.8, 1.6 Hz, 1H), 8.36 (d, J = 4.8 Hz, 1H), 8.01 (br s, 1H), 7.35 (ddd, J = 8.0, 2.5, 1.6 Hz, 1H), 7.19 (ddd, J = 8.1, 4.8, 0.8 Hz, 1H), 6.79 (d, J = 7.8 Hz, 1H), 6.78 (s, 1H), 6.72 (ddd, J = 7.8, 1.8, 0.7 Hz, 1H), 5.96 (d, J = 7.8 Hz, 2H), 3.86–3.71 (m, 2H), 3.68 (br s, 2H), 3.17–3.09 (m, 1H), 2.07–1.88 (m, 3H), 1.32 (s, 9H). 13C NMR (100 MHz, CDCl3) δ ( ppm): 171.4, 169.7, 148.2, 148.2, 147.0, 146.9, 136.9, 132.9, 127.3, 123.1, 122.1, 109.4, 108.6, 101.3, 74.8, 51.4, 50.5, 43.0, 41.4, 28.6, 24.3. IR v (cm−1): 714, 809, 921, 1032, 1100, 1243, 1363, 1418, 1447, 1491, 1542, 1608, 1679, 2892, 2958, 3285. HRMS (FAB+, M+) calcd for C23H28N3O4: [M + 1] 410.2080, found: 410.2090. tert-Butyl (4-(2-(tert-butylcarbamoyl)-2-( pyridin-3-yl)pyrrolidin-1-yl)-4-oxobutyl)carbamate (8t). According to the general procedure, this compound was obtained from the Ugi adduct 6t (0.043 g, 0.1 mmol) as a pale yellow solid in 60% yield (0.026 g, 0.060 mmol). For the cycloisomerization reaction, it was necessary to use 5.0 equiv. of potassium tert-butoxide (0.056 g, 0.50 mmol) and 10 h of reaction. The reduction step was completed in 24 h. Rf 0.50 (2% MeOH–EtOAc) mp: 130–132 °C. 1H NMR (300 MHz, CDCl3) δ ( ppm): 8.46 (dd, J = 4.8, 1.6 Hz, 1H), 8.39 (dd, J = 2.4, 0.9 Hz, 1H), 7.95 (br s, 1H), 7.45 (d, J = 7.9 Hz, 1H), 7.23 (ddd, J = 8.1, 4.8, 0.8 Hz, 1H),

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4.77 (br s, 1H), 3.86–3.64 (m, 2H), 3.27–3.07 (m, 3H), 2.48 (t, J = 7.0 Hz, 2H), 2.11–1.88 (m, 2H), 1.87–1.76 (m, 2H), 1.70 (ddd, J = 12.5, 11.4, 6.3 Hz, 1H), 1.44 (s, 9H), 1.33 (s, 9H). 13C NMR (75 MHz, CDCl3) δ ( ppm): 172.8, 169.9, 156.3, 148.2, 147.0, 137.0, 133.1, 123.1, 79.3, 74.7, 51.4, 50.3, 41.4, 32.8, 29.8, 28.6, 28.5, 25.1, 24.2. IR v (cm−1): 712, 999, 1066, 1138, 1166, 1224, 1254, 1362, 1417, 1428, 1508, 1559, 1606, 1660, 1705, 2934, 2967, 3254, 3388. HRMS (FAB+, M+) calcd for C23H37N4O4: [M + 1] 433.2815, found: 433.2811. N-(tert-Butyl)-1-decanoyl-2-(pyridin-3-yl)pyrrolidine-2-carboxamide (8u). According to the general procedure, this compound was obtained from the Ugi adduct 6u (0.041 g, 0.1 mmol) as a pale yellow oil in 61% yield (0.025 g, 0.061 mmol). For the cycloisomerization reaction, it was necessary to use 5.0 equiv. of potassium tert-butoxide (0.056 g, 0.50 mmol) and 23 h of reaction. The reduction step was completed in 24 h. Rf 0.30 (60% EtOAc–hexanes). 1H NMR (300 MHz, CDCl3) δ ( ppm): 8.46 (dd, J = 4.8, 1.6 Hz, 1H), 8.37 (dd, J = 2.5, 0.9 Hz, 1H), 8.13 (br s, 1H), 7.40 (ddd, J = 8.0, 2.5, 1.6 Hz, 1H), 7.21 (ddd, J = 8.1, 4.8, 0.8 Hz, 1H), 3.83–3.69 (m, 2H), 3.16 (ddd, J = 12.5, 5.6, 2.9 Hz, 1H), 2.42 (t, J = 7.3 Hz, 2H), 2.08–1.89 (m, 2H), 1.72–1.59 (m, 3H), 1.33 (s, 9H), 1.30–1.24 (m, 12H), 0.90–0.86 (m, 3H). 13C NMR (75 MHz, CDCl3) δ ( ppm): 173.7, 170.0, 148.1, 146.9, 137.2, 132.8, 123.1, 74.6, 51.3, 50.4, 41.4, 35.9, 32.0, 29.6, 29.6, 29.5, 29.4, 28.6, 24.9, 24.3, 22.8, 14.2. IR v (cm−1): 662, 712, 803, 1024, 1226, 1363, 1412, 1455, 1552, 1627, 1671, 2854, 2924, 2957, 3058, 3259. HRMS (FAB+, M+) calcd for C24H40N3O2: [M + 1] 402.3121, found: 402.3112. 1-Benzoyl-N-(tert-butyl)-2-( pyridin-4-yl)pyrrolidine-2-carboxamide (8v). Using the general procedure, this compound was obtained from the Ugi adduct 6v (0.035 g, 0.1 mmol) as a pale yellow solid in 66% yield (0.023 g, 0.066 mmol). For the cycloisomerization reaction, it was necessary to use 8 h of reaction and reflux conditions during the reduction step (15 h). Rf 0.35 (30% hexanes–EtOAc). mp: 136–138 °C. 1H NMR (300 MHz, CDCl3) δ ( ppm): 8.59–8.57 (m, 2H), 8.21 (br s, 1H), 7.54–7.45 (m, 5H), 7.20–7.18 (m, 2H), 3.80–3.61 (m, 2H), 3.27–3.20 (m, 1H), 2.03–1.70 (m, 3H), 1.38 (s, 9H). 13C NMR (75 MHz, CDCl3) δ ( ppm): 171.2, 169.3, 150.2, 150.0, 137.0, 130.5, 128.8, 126.4, 120.3, 75.6, 53.3, 51.5, 41.2, 28.6, 24.2. IR v (cm−1) 558, 654, 657, 700, 722, 820, 1232, 1287, 1361, 1417, 1447, 1554, 1598, 1670, 2928, 2959, 2982, 3065, 3243. HRMS (FAB+, M+) calcd for C21H26N3O2: [M + 1] 352.2025, found: 352.2032. 1-Benzoyl-N-(tert-butyl)-2-( pyridin-2-yl)pyrrolidine-2-carboxamide (8w). Using the general procedure, this compound was obtained from the Ugi adduct 6w (0.035 g, 0.1 mmol) as a pale yellow solid in 70% yield (0.0246 g, 0.070 mmol). For the cycloisomerization reaction, it was necessary to use 8 h of reaction and reflux conditions during the reduction step (24 h). Rf 0.45 (50% EtOAc–hexanes), mp: 104–106 °C. 1H NMR (300 MHz, CDCl3) δ ( ppm): 9.01 (br s, 1H), 8.57 (ddd, J = 4.8, 1.9, 0.9 Hz, 1H), 7.68 (ddd, J = 8.1, 7.5, 1.9 Hz, 1H), 7.61 (ddd, J = 4.0, 3.1, 1.6 Hz, 2H), 7.44–7.40 (m, 3H), 7.36 (dd, J = 8.1, 1.0 Hz, 1H), 7.19 (ddd, J = 7.5, 4.8, 1.1 Hz, 1H), 3.79–3.70 (m, 2H), 2.86–2.78 (m, 1H), 2.18–2.09 (m, 1H), 2.01–1.91 (m, 1H),

7080 | Org. Biomol. Chem., 2014, 12, 7068–7082


1.83–1.72 (m, 1H), 1.41 (s, 9H). 13C NMR (75 MHz, CDCl3) δ ( ppm): 170.5, 169.6, 160.8, 148.5, 137.5, 137.0, 128.4, 126.8, 122.0, 121.0, 75.5, 52.6, 51.1, 40.9, 28.7, 24.2. IR v (cm−1): 547, 656, 701, 725, 745, 774, 783, 1225, 1361, 1412, 1550, 1611, 1668, 2875, 2926, 2954, 2974, 3059, 3244. HRMS (FAB+, M+) calcd for C21H26N3O2: [M + 1] 352.2025, found: 352.2018. 1-Benzoyl-N-(tert-butyl)-2-(pyrimidin-5-yl)pyrrolidine-2-carboxamide (8x). Using the general procedure, this compound was obtained from the Ugi adduct 6x (0.035 g, 0.1 mmol) as a pale yellow solid in 40% yield (0.014 g, 0.040 mmol). For the reduction step, it was necessary to use reflux conditions for 12 h. Rf 0.25 (50% EtOAc–hexanes), mp: 139–141 °C. 1H NMR (300 MHz, CDCl3) δ ( ppm): 9.14 (s, 1H), 8.68 (s, 2H), 8.09 (br s, 1H), 7.49–7.48 (m, 5H), 3.81–3.65 (m, 2H), 3.30–3.24 (m, 1H), 2.06–1.76 (m, 3H), 1.38 (s, 9H). 13C NMR (75 MHz, CDCl3) δ ( ppm): 171.4, 168.8, 157.4, 154.1, 136.6, 134.7, 130.7, 128.9, 126.4, 73.0, 53.1, 51.8, 41.3, 28.7, 24.1. IR v (cm−1): 482, 458, 700, 724, 747, 1230, 1286, 1360, 1412, 1448, 1554, 1596, 1678, 2956, 3063, 3251. HRMS (FAB+, M+) calcd for C20H25N4O2: [M + 1] 353.1978, found: 353.1973. 1-Benzoyl-2-( pyridin-3-yl)pyrrolidine-2-carboxamide (13a). A solution of 1-benzoyl-N-(tert-butyl)-2-( pyridin-3-yl)pyrrolidine2-carboxamide 8a (0.035 g, 0.1 mmol) in the BF3·2CH3COOH complex (0.3 mL) was stirred at room temperature until the reaction was completed as indicated by TLC (26 h). The reaction mixture was quenched by addition of ice-water (20 mL), basified with 25% ammonia until pH 11, and extracted with CH2Cl2 (3 × 20 mL). The organic extracts were combined, washed with brine, dried (Na2SO4) and concentrated in vacuo. The crude product was purified by flash column chromatography (15% MeOH–EtOAc) to give 13a as a pale yellow solid in 40% yield (0.0115 g). Rf 0.30 (15% MeOH–EtOAc). mp: 175–177 °C. 1H NMR (300 MHz, CDCl3) δ ( ppm): 8.63 (dd, J = 2.6, 0.9 Hz, 1H), 8.54 (dd, J = 4.8, 1.6 Hz, 1H), 8.04 (br s, 1H), 7.65 (ddd, J = 8.0, 2.5, 1.6 Hz, 1H), 7.57–7.51 (m, 2H), 7.50–7.43 (m, 3H), 7.30 (ddd, J = 8.0, 4.8, 0.8 Hz, 1H), 5.66 (br s, 1H), 3.86–3.73 (m, 1H), 3.72–3.63 (m, 1H), 3.29–3.18 (m, 1H), 2.11–1.83 (m, 3H). 13C NMR (75 MHz, CDCl3) δ ( ppm): 173.2, 171.3, 148.7, 147.0, 136.9, 136.0, 133.2, 130.5, 128.8, 126.6, 123.3, 74.0, 53.2, 41.6, 24.3. IR v (cm−1): 643, 703, 754, 1025, 1111, 1402, 1597, 1611, 1633, 1659, 1691, 2886, 2923, 2957, 3180, 3334. HRMS (FAB+, M+) calcd for C17H18N3O2: [M + 1] 296.1399, found: 296.1394.

Conclusions We have developed the first combinatorial synthesis for nicotine analogs 8a–x from Ugi 4-CR/propargyl adducts 6a–x featuring a one-pot cycloisomerization–reduction process. This protocol allows the rapid preparation of a library of nicotine analogs with different substitution patterns in an efficient and economical fashion. Importantly, this methodology allows the synthesis of analogues with the pyrrolidine ring at non-natural isomeric positions on the pyridine as well as a new nicotine analog with a pyrimidine ring replacing the pyridine motif. We


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believe that this synthetic approach has the potential for widespread use and can significantly contribute to the investigation of new drugs related to nicotine.


Acknowledgements We would like to thank Prof. D. E. Ward and Dr J. M. Muchowski for revising the manuscript and DGAPAUNAM for financial support (grant IN 212513) and a postgraduate scholarship for L. A. Polindara-García. We also thank Marisela Gutierrez and Rosa I. del Villar (F.Q. UNAM), IQ Luis Velasco Ibarra and Dr F. Javier Pérez Florez (Instituto de Química, UNAM) for technical assistance.

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