Diastereoselectivity of Azido-Ugi Reaction with Secondary Amines

30 May 2017 - Danil P. Zarezin , Adil M. Kabylda , Valentina I. Vinogradova , Pavel V. Dorovatovskii , Victor N. Khrustalev , Valentine G. Nenajdenko...
0 downloads 0 Views 1MB Size
Download PDF
Article pubs.acs.org/joc

Diastereoselectivity of Azido-Ugi Reaction with Secondary Amines. Stereoselective Synthesis of Tetrazole Derivatives Danil P. Zarezin,† Victor N. Khrustalev,‡ and Valentine G. Nenajdenko*,† †

Department of Chemistry, Lomonosov Moscow State University, Moscow 119991, Russia RUDN University, Miklukho-Maklay Street, 6, 117198 Moscow, Russia

‡

S Supporting Information *

ABSTRACT: The diastereoselectivity of azido-Ugi reaction with cyclic amines was investigated. It was found that the reaction with α-substituted five- to seven-membered cyclic amines proceeds very efficiently to provide high control of diastereoselectivity (≤100% de) under mild conditions. Target tetrazole-derived products were isolated in excellent yields (≤98%). The reaction has a broad scope in terms of its amine, aldehyde, and isocyanide nature. It was found that the diastereoselectivity of the reaction depends on the ring size of the starting cyclic amines. More rigid piperidines provided the highest selectivity of the reaction. Using benzyl isocyanide, the prepared N-benzyl tetrazoles can be deprotected by hydrogenolysis to form the corresponding NH tetrazoles in high yields.

■

INTRODUCTION Isocyanide functionality is one of the most intriguing functional groups in organic chemistry.1 One of the most important features of isocyanides is the possibility of participating in multicomponent reactions, such as the Passerini and Ugi reaction. These reactions provide the shortest and most efficient route to α-hydroxy acid and α-amino acid derivatives. As a result, a high degree of molecular complexity can be created from simple starting materials in only one synthetic step. It has been demonstrated that application of isocyanides opens very efficient access to a huge variety of valuable molecules for drug discovery. Not only peptides and peptidomimetics but also heterocycles and macroheterocycles can be synthesized very efficiently. Moreover, isocyanides have found broad application in inorganic and coordination chemistry as well as materials science, demonstrating the spectacular success of this functionality.1 The most explored transformation for isocyanides is the Ugi reaction. In spite of the power of this method, it has only one weakness, but it is very significant. This is the problem of stereocontrolled synthesis. However, some limited examples of asymmetric Ugi reaction have been reported recently.2 More progress has been made in the field of asymmetric Passerini reaction.3 In general, control of the diastereoselectivity of the Ugi reaction remains challenging. Of four components (an isocyanide, an aldehyde, an acid, and an amine), only some chiral primary amines4 and chiral cyclic imines5 can provide diastereoselective Ugi reaction. Moreover, the number of such amines affording high diastereoselectivity is very limited. As a rule, these amines are complex molecules that are difficult to prepare or remove from the synthesized products when subsequent nitrogen deprotection is required. An attempt to use simple chiral amines, such as 1-phenylethylamine, resulted © 2017 American Chemical Society

in poor stereocontrol. Other components of the Ugi reaction do not provide the diastereoselectivity at all.6 Nevertheless, we have demonstrated the principal possibility of diastereoselective Ugi reaction without amine using intramolecular cyclization to form a six-membered ring.7 In general, the Ugi reaction with secondary amines has been studied less. Analysis of the literature shows that almost nothing is known about the diastereoselectivity of the Ugi reaction with secondary amines. The lower efficiency of this transformation can be explained by the impossibility of Mumm rearrangement to form stable products. This reaction requires the presence of an additional nucleophile or preliminary preparation of enamines. The progress in this field has been documented recently by Tron.8 We found in the literature an example of intramolecular Ugi reaction with azanorbornene carboxylic acid.9 A special type of bifunctional compound is Yudin’s aziridine aldehyde that exists in dimeric form and has unique reactivity.10 On the other hand, the azido-Ugi reaction with secondary amines leads to the formation of stable tetrazole derivatives.11 Therefore, we decided to use this approach to obtain information about the diastereoselectivity of the Ugi reaction with secondary amines. Tetrazoles attract a great deal of attention because of their broad applications in medicinal chemistry and pharmacology,12 materials chemistry (e.g., as highly energetic compounds13), organocatalysis,14 and organometallic and coordination chemistry.15 Recently, the azido-Ugi reaction with cyclic imines has been studied to open access to a new family of organocatalysts containing a tetrazolyl moiety.16 Also, the fragment of cyclic Received: March 15, 2017 Published: May 30, 2017 6100

DOI: 10.1021/acs.joc.7b00611 J. Org. Chem. 2017, 82, 6100−6107

Article

The Journal of Organic Chemistry

Scheme 3. Reaction with 2-Substituted Pyrrolidinesa

amines bearing tetrazoles is an important structural unit that varies in biologically active compounds.17

■

RESULTS AND DISCUSSION Cyclic amines have conformational behavior that is more predictable than that of other secondary amines. Therefore, we expected to achieve diastereoselective construction of tetrazole derivatives using the azido-Ugi reaction with α-substituted cyclic amines. According to Scheme 1, preferable formation of diastereomers having a rel-S,S configuration is expected because of shielding of one face of the iminium cation with substituent R1. Scheme 1. Predicted Stereochemistry of the Reaction

To search for optimal reaction conditions, a model fourcomponent reaction among the hydrochloride of L-proline methyl ester, isobutyric aldehyde, benzyl isocyanide, and TMSN3 (as the HN3 source) was investigated. Et3N (1.5 equiv) was used as a base to neutralize HCl. Performing the reaction in aprotic solvents such as THF, MeCN, DCM, and toluene resulted in the formation of a complex mixture of unidentified products. In the case of alcohols (MeOH, EtOH, iPrOH, and tBuOH), the reaction proceeded very cleanly and isolated yields of desired compounds ranged from 86 to 96% at rt. A mixture of two diastereomers in a 3.2:1 ratio was obtained at rt regardless of the alcohol used (Scheme 2). The reaction at

a

The relative or absolute configuration of the major diastereomer is given.

These new compounds are attractive small molecules in terms of the examination of their biological activity because all parameters of these compounds matched the Lipinski rule of 5.18 The possibility of efficiently constructing these compounds from three independent building blocks (an amine, an aldehyde, and an isocyanide) should be mentioned. The observed diastereoselectivity depends on the steric bulkiness of the substituent at the α position of the starting pyrrolidine. Moreover, the ratio of diastereomers correlates perfectly with conformational energy (A value) of a substituent at the α position.19 Nice stereoselectivity (dr of >40:1) was observed when the A value was >2 kcal/mol. In the case of 2phenylpyrrolidine, the dr was slightly lower (dr of 10:1). Some stacking interactions probably play an additional role in this case. It should be noted that a mixture of diastereomers can be separated easily using conventional column chromatography. Next, the configuration (relative and absolute) of the obtained tetrazoles was established. For this purpose, a single crystal of compound 4c was prepared. This amine derived from natural S-proline has a known configuration. X-ray diffraction data confirmed the proposed structure of 4c (Figure 1). A strong H-bond between hydroxyl and pyrrolidine nitrogen is observed in the crystal. Moreover, the obtained data confirmed perfectly our stereochemical model (Scheme 1), predicting correctly the relative configuration of the products. To our delight, the scope of the reaction in terms of amine structure was found to be very broad. Not only pyrrolidines but also piperidines and azepanes (1i−u) reacted smoothly to give target molecules 4r−u in excellent isolated yields (≤90%) (Scheme 4). A much better stereochemical outcome was observed for the reaction with substituted piperidines. As a rule, the formation of a single diastereomer was observed. Only in cases of piperidines having flexible substituents with free rotation (n-Pr and methoxymethyl) the diastereoselectivity was moderate. In contrast, the azido-Ugi reaction with α-substituted azepanes resulted in diastereoselectivity that was lower than that of pyrrolidines. Very indicative results were obtained for 2-

Scheme 2. Optimization of the Reaction

a lower temperature (4 °C) gave the same ratio of diastereomers in methanol and i-PrOH, while the improvement in diastereoselectivity was observed (5:1) in tert-butanol in spite of the solvent solidifying at this temperature. The same selectivity was observed at −18 °C. A standard version of the Ugi reaction was also performed with some carboxylic acids (AcOH, PhCO2H, and CF3CO2H). However, only in the case of the reaction with acetic acid the corresponding product 4′ was isolated in moderate yield (53%) with a dr of 3:1; other acids gave a complex mixture of products. With optimal reaction conditions in hand, we started to investigate the influence of different components on the scope of the reaction and diastereoselectivity dependence. Various cyclic amines 1a−h having different substituents at the α position (Scheme 3) and ring size were studied first (free base or hydrochloride). It was found that the azido-Ugi reaction of isobutyraldehyde and benzyl isocyanide with various αsubstituted pyrrolidines proceeded very efficiently to give target tetrazole derivatives 4a−h in excellent isolated yields (≤98%). 6101

DOI: 10.1021/acs.joc.7b00611 J. Org. Chem. 2017, 82, 6100−6107

Article

The Journal of Organic Chemistry Scheme 5. Scope of Aldehydesa

Figure 1. Molecular structure of 4c. Thermal ellipsoids are shown at the 50% probability level.

Scheme 4. Reaction with Piperidines and Azepanesa

a

a

The relative configuration of the major diastereomer is given.

(≤90%). To our surprise, only in the case of pivalic aldehyde did the yield decrease. Next, a variety of isocyanides (3a−g) was studied in the reaction with 2-phenylpiperidine and isobutyraldehyde. The reaction proceeded well with hindered, acidic, unsaturated, and nonracemizable chiral isocyanides20 having additional functionality in the structure (Scheme 6). No restrictions were found in any case. Moreover, the reaction gave single isomers 4q and 4ac−ai for almost all isocyanides studied. Finally, the possibility of preparing 5-unsubstituted tetrazoles using deprotection of N-benzyltetrazoles by hydrogenolysis was demonstrated. NH-tetrazoles are known to be popular bioisosteres with a carboxylic group having similar pKa values but higher lipophilicities. Previously, we demonstrated clean deprotection of N-benzyltetrazoles by hydrogenolysis using Pd/ C as a catalyst.16 Three chiral N-benzyltetrazoles, 4a, 4c, and 4m, derived from proline and nicotine were converted smoothly to the corresponding NH-tetrazoles (Scheme 7). The reaction proceeded without epimerization. In summary, the azido-Ugi reaction with α-substituted fiveto seven-membered cyclic amines proceeds very efficiently to provide a high degree of diastereocontrol (≤100% de). Target tetrazole derivatives can be isolated in excellent yields (≤98%). The reaction has a broad scope in terms of amines, aldehydes, and isocyanides. A new diastereoselective protocol for the synthesis of tetrazolyl-substituted cyclic amines was elaborated. Deprotection of prepared N-benzyl-substituted tetrazoles by hydrogenolysis opens access to the corresponding NHtetrazoles in high yields. Moreover, this approach can be used for the synthesis of a family of valuable tetrazole derivatives.

The relative configuration of the major diastereomer is given.

cyclohexyl-substituted amines 1i, 1k, and 1s. The formation of a single diastereomer was observed for pyrrolidine 1i and piperidine 1k, whereas a lower dr of 10:1 was observed in the case of 2-cyclohexylazepane 1s. These results are in good agreement with stereochemical peculiarities of saturated nitrogen heterocycles. A more flexible seven-membered ring resulted in a lower diastereoselectivity. On the other hand, predictable stereochemical behavior of five- or six-membered nitrogen heterocycles resulted in greater stereocontrol. Then, the influence of an aldehyde component (2a−h) was investigated (Scheme 5). 2-Phenylpiperidine and benzyl isocyanide were chosen as model inputs. The reaction with several aromatic and aliphatic aldehydes demonstrated a high synthetic effectiveness. As a rule, the reaction resulted in formation of a single diastereomer in all studied cases. Moreover, target products were isolated in high yields

■

EXPERIMENTAL SECTION

One-dimensional NMR (1H, 19F, and 13C) spectra were recorded on 400 MHz spectrometers. Chemical shifts are reported in parts per million downfield from TMS. Deuterated solvent peaks were used as internal references: deuterochloroform at 7.27 and 77.00 ppm, deutero-DMSO at 2.50 and 39.50 ppm, and deuteromethanol at 3.31 and 49.00 ppm. Chemical shifts for 19F NMR data are referenced to CFCl3 (0.0 ppm) or PhCF3 (−63.90 ppm). High-resolution mass spectrometry (HRMS) was performed using a MicroTOF-Q instru6102

DOI: 10.1021/acs.joc.7b00611 J. Org. Chem. 2017, 82, 6100−6107

Article

The Journal of Organic Chemistry Scheme 6. Scope of Isocyanidesa

a

The relative configuration of the major diastereomer is given.

Scheme 7. Deprotection of N-Benzyltetrazoles

When the reaction was complete, the solvent was evaporated and the product was purified by column chromatography [dichloromethane/ methanol (30:1) or dichloromethane]. (S)-Methyl 1-[(S)-1-(1-Benzyl-1H-tetrazol-5-yl)-2-methylpropyl]pyrrolidine-2-carboxylate (4a). White solid, 59 mg, 86%. Mp: 55− 57 °C. 1H NMR (400 MHz, CDCl3): δ 0.11 (d, JHH = 6.6 Hz, 3H), 0.98 (d, JHH = 6.6 Hz, 3H), 1.59−1.62 (m, 1H), 1.73−1.76 (m, 2H), 1.87−1.93 (m, 1H), 2.23−2.29 (m, 1H), 2.83 (dd, JHH = 6.0 Hz, JHH = 2.1 Hz, 1H), 3.03−3.06 (m, 2H), 3.70 (s, 3H), 3.83 (d, JHH = 10.6 Hz, 1H), 5.44 (d, JHH = 15.4 Hz, 1H), 5.72 (d, JHH = 15.4 Hz, 1H), 7.19− 7.31 (m, 5H). 13C NMR (100 MHz, CDCl3): δ 19.2, 19.8, 23.3, 28.8, 31.1, 46.1, 50.7, 51.9, 58.8, 62.1, 127.7, 128.8, 128.9, 133.8, 153.5, 174.1. IR (ZnSe): 705, 719, 1451, 1725, 2950 cm−1. HRMS (ESI): calcd for C18H26N5O2 [M + H]+ 344.2087, found 344.2082. [α]20D = −20.6° (c 0.94, CH2Cl2). Rel 5-{(S)-1-[(S)-2-tert-Butylpyrrolidin-1-yl]-2-methylpropyl}-1benzyl-1H-tetrazole (4b). White solid, 61 mg, 90%. Mp: 139−141 °C. 1H NMR (400 MHz, CDCl3): δ 0.19 (d, J = 6.6 Hz, 3H), 0.80 (s, 9H), 1.16 (d, J = 6.6 Hz, 3H), 1.18−1.30 (m, 2H), 1.40−1.54 (m, 2H), 2.06−2.09 (m, 1H), 2.22−2.30 (m, 1H), 2.85−2.87 (m, 1H), 3.57−3.59 (m, 1H), 3.70 (d, J = 10.76 Hz, 1H), 5.51 (d, JHH = 15.6 Hz, 1H), 5.72 (d, JHH = 15.6 Hz, 1H), 7.18−7.35 (m, 5H). 13C NMR (100 MHz, CDCl3): δ 19.6, 20.4, 25.2, 26.9, 27.3, 32.9, 36.7, 47.3, 50.8, 63.3, 71.0, 127.3, 128.9, 129.1, 134.0, 153.5. IR (ZnSe): 698, 723, 2867, 2960 cm−1. HRMS (ESI): calcd for C20H32N5 [M + H]+ 342.2658, found 342.2645. {(S)-1-[(S)-1-(1-Benzyl-1H-tetrazol-5-yl)-2-methylpropyl]pyrrolidin-2-yl}diphenylmethanol (4c). White solid, 68 mg, 73%. Mp: 165−167 °C. 1H NMR (400 MHz, CDCl3): δ 0.07 (d, JHH = 6.7 Hz, 3H), 1.03 (d, J = 6.7 Hz, 3H), 1.34−1.42 (m, 1H), 1.55−1.64 (m, 3H), 2.16−2.26 (m, 1H), 3.02 (d, JHH = 10.5 Hz, 1H), 3.06−3.11 (m, 1H), 3.53−3.56 (m, 1H), 3.84−3.90 (m, 1H), 4.49 (s, 1H), 5.06 (d, JHH = 15.9 Hz, 1H), 5.42 (d, JHH = 15.8 Hz, 1H), 7.02−7.04 (m, 2H), 7.12−7.37 (m, 11H), 7.56 (d, JHH = 7.5 Hz, 2H). 13C NMR (100 MHz, CDCl3): δ 19.6, 20.3, 24.8, 30.1, 32.8, 48.2, 49.9, 61.4, 70.6, 78.5, 125.7, 126.1, 126.3, 126.7, 126.9, 127.7, 128.3, 128.5, 128.9, 134.0, 145.3, 147.9, 155.0. IR (ZnSe): 708, 2960, 3455 cm−1. HRMS (ESI): calcd for C29H34N5O [M + H]+ 468.2758, found 468.2766. [α]20D = −1.3° (c 0.46, CH2Cl2). Rel 1-Benzyl-5-{(S)-1-[(S)-2-(methoxymethyl)pyrrolidin-1-yl]-2methylpropyl}-1H-tetrazole (4d). Yellow oil, 54 mg, 82%. 1H NMR (400 MHz, CDCl3): δ −0.02 (d, JHH = 6.6 Hz, 3H), 0.96 (d, JHH = 6.6

ment. Electrospray ionization (ESI) mass spectrometry (MS) was performed using dichloromethane or methanol solutions. Melting points are uncorrected. The silica gel used for flash chromatography was 230−400 mesh. (S)-Methyl 1-[(S)-1-Acetoxy-1-(benzylimino)-3-methylbutan2-yl]pyrrolidine-2-carboxylate (4′). The title compound was prepared using standard conditions of Ugi reaction (38 mg, 53%, brown oil; two diastereomers in a 3:1 ratio) (signals of minor rotomer in parentheses). 1H NMR (400 MHz, CDCl3): δ 0.70 (0.77) (d, JHH = 6.6 Hz, 3H), 0.96 (0.93) (d, JHH = 6.6 Hz, 3H), 1.70−1.99 (1.67− 1.74) (m, 4H), 2.14−2.20 (2.01−2.04) (m, 1H), 2.38 (2.34) (s, 3H), 2.80−2.88 (2.95−2.97) (m, 1H), 3.04−3.08 (3.25−3.28) (m, 1H), 3.48 (3.99) (dd, JHH = 5.4 Hz, JHH = 2.8 Hz, 1H), 3.69 (3.64) (s, 3H), 4.08 (4.29) (d, JHH = 10.2 Hz, 1H), 4.75 (4.88) (d, JHH = 16.5 Hz, 1H), 5.19 (5.04) (d, JHH = 16.5 Hz, 1H), 7.18−7.34 (7.18−7.34) (m, 5H). 13C NMR (100 MHz, CDCl3): δ 19.3, 19.5, 23.5, 26.4, 28.6, 30.0, 47.4, 47.5, 51.7, 61.2, 66.5, 126.7, 127.4, 128.7, 137.2, 174.1, 174.8, 175.9. IR (ZnSe): 702, 1176, 1704 (CO), 1743, 2960 cm−1. HRMS (ESI): calcd for C20H29O4N2 [M + H]+ 361.2122, found 361.2123. General Procedure for the Azido-Ugi Reaction. The appropriate amine (1a−u) (0.2 mmol) was dissolved in t-BuOH (5 mL) or MeOH (in the case of 4q and 4ab) (5 mL). Triethylamine (1.5 equiv) was used in the reaction with the hydrochloride of Lproline methyl ester and the hydrochloride of anabasine to neutralize molecules of HCl. The aldehyde (0.22 mmol) (2a−h), TMSN3 (0.22 mmol), and isocyanide (3a−h) (0.22 mmol) were added, and the solution was kept for 1 day (TLC control) at 4 °C (refrigerator). 6103

DOI: 10.1021/acs.joc.7b00611 J. Org. Chem. 2017, 82, 6100−6107

Article

The Journal of Organic Chemistry

0.30−0.33 (m, 1H), 0.86 (s, 9H), 1.10 (d, JHH = 6.7 Hz, 3H), 1.14− 1.34 (m, 4H), 1.64−1.69 (m, 1H) 1.56 (t, JHH = 7.0 Hz, 1H), 2.53− 2.59 (m, 1H), 2.80−2.88 (m, 1H), 3.22 (dd, JHH = 9.1 Hz, JHH = 5.7 Hz, 1H), 3.49 (d, J = 10.8 Hz, 1H), 5.71 (dd, JHH = 24.0 Hz, JHH = 15.6 Hz, 2H), 7.21−7.35 (m, 5H). 13C NMR (100 MHz, CDCl3): δ 19.2, 19.9, 20.2, 21.9, 22.4, 27.7, 31.3, 38.4, 39.1, 51.1, 65.6, 127.5, 128.9, 129.1, 133.9, 157.5. IR (ZnSe): 696, 723, 1107, 2866, 2954 cm−1. HRMS (ESI): calcd for C21H34N5 [M + H]+ 356.2814, found 356.2810. Rel (S)-1-[(S)-1-(1-Benzyl-1H-tetrazol-5-yl)-2-methylpropyl]-2-cyclohexylpiperidine (4k). White solid, 68 mg, 89%. Mp: 113−115 °C. 1 H NMR (400 MHz, CDCl3): δ 0.27 (d, JHH = 6.5 Hz, 3H), 1.00 (d, JHH = 6.5 Hz, 3H), 1.04−1.90 (m, 18H), 2.40−2.47 (m, 2H), 3.05− 3.08 (m, 1H), 3.75 (d, JHH = 10.2 Hz, 1H), 5.39 (d, JHH = 15.6 Hz, 1H), 5.75 (d, JHH = 15.6 Hz, 1H), 7.18−7.35 (m, 5H). 13C NMR (100 MHz, CDCl3): δ 19.8, 20.2, 23.0, 25.1, 25.3, 26.7, 26.8, 27.1, 30.4, 30.6, 38.6, 45.5, 50.8, 59.2, 62.8, 127.3, 128.8, 129.0, 133.8, 154.7. IR (ZnSe): 698, 1442, 2843, 2924 cm−1. HRMS (ESI): calcd for C23H36N5 [M + H]+ 382.2971, found 382.2969. Rel (S)-2-Benzhydryl-1-[(S)-1-(1-benzyl-1H-tetrazol-5-yl)-2methylpropyl]piperidine (4l). White solid, 83 mg, 89%. Mp: 180− 182 °C. 1H NMR (400 MHz, CDCl3): δ 0.19 (d, JHH = 6.6 Hz, 3H), 0.25 (d, JHH = 6.6 Hz, 3H), 0.58−0.66 (m, 1H), 1.08 (d, JHH = 13.4 Hz, 1H), 1.22−1.29 (m, 2H), 1.48−1.56 (m, 2H), 2.23−2.29 (m, 1H), 3.01−3.03 (m, 2H), 3.22−3.26 (m, 1H), 3.45 (d, JHH = 9.7 Hz, 1H), 4.39 (d, JHH = 10.5 Hz, 1H), 5.53 (dd, JHH = 15.6 Hz, JHH = 16.6 Hz, 2H), 7.09−7.16 (m, 4H), 7.21−7.28 (m, 6H), 7.31−7.34 (m, 2H), 7.43−7.48 (m, 3H). 13C NMR (100 MHz, CDCl3): δ 18.6, 19.3, 22.2, 24.0, 30.6, 39.7, 51.0, 52.1, 62.0, 64.6, 126.1, 126.2, 127.7, 127.8, 128.0, 128.4, 128.5, 129.0, 129.2, 133.9, 142.7, 144.5, 157.0. IR (ZnSe): 702, 1448, 1495, 2925 cm−1. HRMS (ESI): calcd for C30H36N5 [M + H]+ 466.2971, found 466.2965. 2-{(S)-1-[(S)-1-(1-Benzyl-1H-tetrazol-5-yl)-2-methylpropyl]piperidin-2-yl}pyridine (4m). Yellow solid, 67 mg, 89%. Mp: 118−120 °C. 1H NMR (400 MHz, CDCl3): δ −0.35 (d, JHH = 6.7 Hz, 3H), 0.99 (d, JHH = 6.7 Hz, 3H), 1.09−1.18 (m, 1H), 1.31−1.52 (m, 2H), 1.57− 1.70 (m, 3H), 2.25−2.35 (m, 1H), 2.40−2.47 (m, 1H), 2.94 (dd, JHH = 2.3 Hz, JHH = 8.4 Hz, 1H), 3.26 (d, JHH = 10.7 Hz, 1H), 3.42 (d, JHH = 10.6 Hz, 1H), 3.15 (d, JHH = 15.3 Hz, 1H), 5.40 (d, JHH = 15.3 Hz, 1H), 6.49 (d, JHH = 7.0 Hz, 2H), 7.05−7.12 (m, 3H), 7.37 (dd, JHH = 2.9 Hz, JHH = 4.8 Hz, 1H), 7.71 (d, JHH = 7.8 Hz, 1H), 8.57−8.60 (m, 2H). 13C NMR (100 MHz, CDCl3): δ 19.1, 19.8, 24.6, 25.8, 30.0, 39.3, 46.3, 50.8, 59.0, 63.2, 123.9, 127.5, 128.7, 128.8, 133.2, 135.3, 140.3, 149.0, 149.5, 152.9. IR (ZnSe): 723, 1425, 2933 cm−1. HRMS (ESI): calcd for C22H29N6 [M + H]+ 377.2454, found 377.2450. [α]20D = −33.0° (c 0.92, CH2Cl2). Rel (R)-1-[(S)-1-(1-Benzyl-1H-tetrazol-5-yl)-2-methylpropyl]-2propylpiperidine (4n). White solid, 57 mg, 84%. Mp: 109−111 °C. 1 H NMR (400 MHz, CDCl3): δ 0.31 (d, JHH = 6.6 Hz, 3H), 0.89 (t, JHH = 7.1 Hz, 3H), 0.98 (d, JHH = 6.6 Hz, 3H), 1.06−1.25 (m, 3H), 1.31−1.44 (m, 3H), 1.49−1.63 (m, 4H), 2.05−2.12 (m, 1H), 2.17− 2.25 (m, 1H), 2.38−2.47 (m, 1H), 3.03−3.09 (m, 1H), 3.78 (d, JHH = 10.1 Hz, 1H), 5.41 (d, JHH = 15.7 Hz, 1H), 5.77 (d, JHH = 15.7 Hz, 1H), 7.15−7.19 (m, 2H), 7.31−7.37 (m, 3H). 13C NMR (100 MHz, CDCl3): δ 14.7, 18.1, 19.8, 20.2, 23.3, 25.9, 29.8, 31.0, 34.9, 46.4, 50.8, 57.5, 58.9, 127.2, 128.8, 129.0, 133.8, 154.2. IR (ZnSe): 694, 721, 1105, 1444, 2921 cm−1. HRMS (ESI): calcd for C20H32N5 [M + H]+ 342.2658, found 342.2657. Rel (S)-1-[(S)-1-(1-Benzyl-1H-tetrazol-5-yl)-2-methylpropyl]-2(pentan-3-yl)piperidine (4o). White solid, 57 mg, 77%. Mp: 73−75 °C. 1H NMR (400 MHz, CDCl3): δ 0.23 (d, JHH = 6.6 Hz, 3H), 1.00 (t, JHH = 7.4 Hz, 3H), 0.95−1.03 (m, 7H), 1.48−1.71 (m, 4H), 1.06− 1.40 (m, 5H), 1.74−1.85 (m, 1H), 2.01−2.06 (m, 1H), 2.41−2.47 (m, 2H), 3.13−3.18 (m, 1H), 3.73 (d, JHH = 10.5 Hz, 1H), 5.43 (d, JHH = 15.4 Hz, 1H), 5.73 (d, JHH = 15.4 Hz, 1H), 7.23−7.36 (m, 5H). 13C NMR (100 MHz, CDCl3): δ 12.1, 13.3, 19.9, 20.0, 21.1, 23.7, 23.9, 24.8, 25.7, 30.5, 41.2, 46.2, 51.1, 58.5, 60.1, 127.7, 128.9, 129.0, 133.5, 154.4. IR (ZnSe): 699, 720, 1456, 2960 cm−1. HRMS (ESI): calcd for C22H36N5 [M + H]+ 370.2971, found 370.2967.

Hz, 3H), 1.19−1.26 (m, 1H), 1.35−1.43 (m, 1H), 1.49−1.59 (m, 2H), 2.13−2.22 (m, 1H), 2.44−2.51 (m, 1H), 2.90−3.03 (m, 2H), 3.30 (t, JHH = 8.5 Hz, 1H), 3.38 (s, 3H), 3.39−3.42 (m, 1H), 4.14 (d, JHH = 11.0 Hz, 1H), 5.69 (dd, JHH = 15.2 Hz, JHH = 3.4 Hz, 2H), 7.18−7.28 (m, 5H). 13C NMR (100 MHz, CDCl3): δ 19.3, 20.1, 23.1, 28.4, 30.8, 46.5, 50.2, 58.9, 59.3, 79.8, 127.7, 128.4, 128.7, 134.4, 153.9. IR (ZnSe): 701, 719, 1095, 1454, 2871, 2960 cm−1. HRMS (ESI): calcd for C18H28N5O [M + H]+ 330.2294, found 330.2290. Rel 1-Benzyl-5-{(S)-2-methyl-1-[(S)-2-phenylpyrrolidin-1-yl]propyl}-1H-tetrazole (4e). White solid, 69 mg, 96%. Mp: 131−133 °C. 1H NMR (400 MHz, CDCl3): δ −0.19 (d, JHH = 6.6 Hz, 3H), 1.08 (d, JHH = 6.6 Hz, 3H), 1.54−1.72 (m, 2H), 1.80−1.87 (m, 1H), 2.02− 2.08 (m, 1H), 2.29−2.37 (m, 1H), 3.06−3.18 (m, 2H), 3.22−3.27 (m, 1H), 3.48 (d, JHH = 11.0 Hz, 1H), 4.56 (d, JHH = 15.3 Hz, 1H), 5.57 (d, JHH = 15.3 Hz, 1H), 6.58 (d, JHH = 7.2 Hz, 2H), 7.14−7.23 (m, 3H), 7.37−7.49 (m, 5H). 13C NMR (100 MHz, CDCl3): δ 19.1, 20.1, 22.2, 31.0, 36.2, 44.8, 50.8, 56.9, 65.5,127.3, 127.5, 127.8, 128.6, 128.7, 128.9, 133.6, 143.1, 153.4. IR (ZnSe): 706, 720, 757, 1457, 2960 cm−1. HRMS (ESI): calcd for C22H28N5 [M + H]+ 362.2345, found 362.2340. Rel 1-Benzyl-5-{(S)-1-[(S)-2-cyclohexylpyrrolidin-1-yl]-2-methylpropyl}-1H-tetrazole (4f). White oil, 72 mg, 98%. 1H NMR (400 MHz, CDCl3): δ 0.21 (d, JHH = 6.6 Hz, 3H), 0.83−0.92 (m, 2H), 1.02 (d, JHH = 6.6 Hz, 3H), 1.09−1.49 (m, 9H), 1.69−1.68 (m, 4H), 2.03− 2.05 (m, 1H), 2.29−2.35 (m, 1H), 2.93−2.95 (m, 1H), 3.03−3.05 (m, 1H), 3.58 (d, J = 10.76 Hz, 1H), 5.29 (d, JHH = 15.5 Hz, 1H), 5.72 (d, JHH = 15.5 Hz, 1H), 7.18−7.36 (m, 5H). 13C NMR (100 MHz, CDCl3): δ 19.7, 20.4, 23.7, 26.1, 26.2, 26.4, 26.9, 27.0, 30.8, 31.4, 40.5, 46.2, 50.8, 58.8, 64.5, 127.4, 128.9, 129.1, 133.8, 154.3. IR (ZnSe): 720, 1106, 1448, 2851, 2925 cm−1. HRMS (ESI): calcd for C22H34N5 [M + H]+ 368.2814, found 368.2805. Rel 1-Benzyl-5-{(S)-1-[(S)-2-(trifluoromethyl)pyrrolidin-1-yl]-2methylpropyl}-1H-tetrazole (4g). White solid, 56 mg, 79%. Mp: 120−122 °C. 1H NMR (400 MHz, CDCl3): δ 0.23 (d, JHH = 6.6 Hz, 3H), 1.07 (d, JHH = 6.6 Hz, 3H), 1.43−1.53 (m, 1H), 1.58−1.64 (m, 1H), 1.66−1.75 (m, 2H), 2.20−2.29 (m, 1H), 2.45−2.53 (m, 1H), 3.03−3.08 (m, 1H), 3.32−3.39 (m, 1H), 3.85 (d, J = 10.9 Hz, 1H), 5.59 (d, JHH = 15.4 Hz, 1H), 5.61 (d, JHH = 15.4 Hz, 1H), 7.23−7.36 (m, 5H). 13C NMR (100 MHz, CDCl3): δ 19.3, 19.8, 23.6, 26.3, 31.8, 46.3, 51.0, 60.2, 61.0 (q, CH-CF3, 2JCF = 30.0 Hz), 126.8 (q, CF3, 1JCF = 280.8 Hz), 127.7, 129.1, 129.2, 133.5, 154.0. 19F NMR (376.5 MHz, CDCl3): δ −75.77 (CF3). IR (ZnSe): 696, 719, 1124, 1278, 1452, 2966 cm−1. HRMS (ESI): calcd for C17H23F3N5 [M + H]+ 354.1900, found 354.1902. Rel 1-Benzyl-5-{(S)-1-[(S)-2-isobutylpyrrolidin-1-yl]-2-methylpropyl}-1H-tetrazole (4h). White solid, 65 mg, 95%. Mp: 76−78 °C. 1H NMR (400 MHz, CDCl3): δ 0.14 (d, JHH = 6.6 Hz, 3H), 0.91 (d, JHH = 6.6 Hz, 3H), 0.99 (t, JHH = 7.2 Hz, 6H), 1.19−1.26 (m, 1H), 1.36− 1.54 (m, 3H), 1.60−1.69 (m, 3H), 2.23−2.33 (m, 2H), 2.96−3.00 (m, 2H), 3.62 (d, J = 10.6 Hz, 1H), 5.29 (d, JHH = 15.4 Hz, 1H), 5.81 (d, JHH = 15.4 Hz, 1H), 7.20−7.22 (m, 2H), 7.33−7.38 (m, 3H). 13C NMR (100 MHz, CDCl3): δ 19.6, 20.3, 22.4, 22.7, 24.5, 25.9, 30.9, 31.0, 44.4, 45.8, 50.9, 58.2, 58.6, 127.6, 128.9, 129.1, 133.8, 154.0. IR (ZnSe): 719, 1105, 1454, 2870, 2956 cm−1. HRMS (ESI): calcd for C20H32N5 [M + H]+ 342.2658, found 342.2657. Rel (R)-1-{(S)-1-[1-Benzyl-1H-tetrazol-5-yl]-2-methylpropyl}-2methylpiperidine (4i). White solid, 55 mg, 88%. Mp: 132−134 °C. 1 H NMR (400 MHz, CDCl3): δ 0.27 (d, JHH = 6.5 Hz, 3H), 0.83 (d, JHH = 5.6 Hz, 3H), 0.98 (d, JHH = 6.5 Hz, 3H), 1.04−1.20 (m, 3H), 1.43−1.46 (m, 1H) 1.56 (d, JHH = 12.3 Hz, 1H), 1.82−1.88 (m, 1H), 2.05 (t, JHH = 10.7 Hz, 1H), 2.41−2.43 (m, 1H), 2.58 (d, JHH = 9.7 Hz, 1H), 2.88 (d, JHH = 11.4 Hz, 1H), 3.38 (d, JHH = 10.4 Hz, 1H), 5.43 (d, JHH = 15.5 Hz, 1H), 5.71 (d, JHH = 15.5 Hz, 1H),7.20−7.36 (m, 5H). 13C NMR (100 MHz, CDCl3): δ 19.7, 19.3, 21.8, 29.3, 30.7, 34.3, 34.7, 46.9, 51.0, 52.4, 65.0, 127.8, 128.8, 129.0, 133.8, 153.3. IR (ZnSe): 707, 717, 1456, 2916 cm−1. HRMS (ESI): calcd for C18H28N5 [M + H]+ 314.2345, found 314.2349. Rel (S)-2-tert-Butyl-1-[(S)-1-(1-benzyl-1H-tetrazol-5-yl)-2methylpropyl]piperidine (4j). White solid, 58 mg, 81%. Mp: 126− 128 °C. 1H NMR (400 MHz, CDCl3): δ 0.25 (d, JHH = 6.7 Hz, 3H), 6104

DOI: 10.1021/acs.joc.7b00611 J. Org. Chem. 2017, 82, 6100−6107

Article

The Journal of Organic Chemistry

CDCl3): δ 14.0, 19.5, 20.4, 22.6, 23.5, 26.6, 29.0, 29.7, 29.9, 30.5, 30.7, 31.9, 33.5, 45.7, 51.0, 60.4, 61.8, 127.4, 128.9, 129.0, 133.9, 155.2. IR (ZnSe): 696, 719, 1113, 1450, 2924 cm−1. HRMS (ESI): calcd for C24H40N5 [M + H]+ 398.3284, found 398.3274. Rel (S)-1-[(S)-1-(1-Benzyl-1H-tetrazol-5-yl)ethyl]-2-phenylpiperidine (4v). Brown oil, 49 mg, 70%. 1H NMR (400 MHz, CDCl3): δ 0.99 (d, JHH = 7.1 Hz, 3H), 1.26−1.82 (m, 8H), 2.87 (dt, JHH = 2.4 Hz, JHH = 9.6 Hz, 1H), 3.03 (dd, JHH = 2.8 Hz, JHH = 8.0 Hz, 1H), 3.30− 3.32 (m, 1H), 4.02 (d, JHH = 15.5 Hz, 1H), 4.12 (q, JHH = 7.1 Hz, 1H), 5.41 (d, JHH = 15.5 Hz, 1H), 6.68−7.41 (m, 10H). 13C NMR (100 MHz, CDCl3): δ 17.0, 24.8, 26.3, 37.8, 47.2, 48.9, 50.5, 66.1, 127.3, 127.4, 127.5, 128.6, 128.9, 129.0, 133.7, 144.0, 155.0. IR (ZnSe): 704, 724, 2868, 2963 cm−1. HRMS (ESI): calcd for C21H26N5 [M + H]+ 348.2188, found 348.2185. Rel (S)-1-[(S)-1-(1-Benzyl-1H-tetrazol-5-yl)-2,2-dimethylpropyl]-2phenylpiperidine (4w). White solid, 25 mg, 31%. Mp: 172−174 °C. 1 H NMR (400 MHz, CDCl3): δ 0.72 (s, 9H), 1.23−1.29 (m, 1H), 1.61−1.74 (m, 5H), 2.24−2.33 (m, 1H), 2.96−2.99 (m, 1H), 3.71− 3.74 (m, 1H), 3.85 (s, 1H), 4.60 (d, JHH = 15.8 Hz, 1H), 5.42 (d, JHH = 15.7 Hz, 1H), 6.67 (d, J1 = 6.5 Hz, 2H), 7.15−7.21 (m, 3H), 7.38− 7.48 (m, 5H). 13C NMR (100 MHz, CDCl3): δ 25.1, 26.1, 28.6, 36.8, 39.2, 50.6, 51.2, 60.2, 68.5, 127.6, 127.7, 128.5, 128.5, 128.7, 128.8, 133.7, 144.7, 151.8. IR (ZnSe): 705, 760, 1362, 2933 cm−1. HRMS (ESI): calcd for C24H32N5 [M + H]+ 390.2658, found 390.2657. Rel (S)-1-[(S)-(1-Benzyl-1H-tetrazol-5-yl)(cyclohexyl)methyl]-2phenylpiperidine (4x). Brown solid, 72 g, 87%. Mp: 155−157 °C. 1 H NMR (400 MHz, CDCl3): δ −0.73 to −0.64 (m, 1H), 0.06 (d, JHH = 12.4 Hz, 1H), 0.75−0.89 (m, 3H), 1.06−1.26 (m, 3H), 1.36−1.60 (m, 3H), 1.63−1.79 (m, 4H), 1.97−2.10 (m, 1H), 2.36 (JHH = 13.0 Hz, 1H), 2.51−2.57 (m, 1H), 2.92 (dd, JHH = 2.5 Hz, JHH = 8.2 Hz, 1H), 3.32 (d, JHH = 12.0 Hz, 1H), 3.77 (d, JHH = 10.7 Hz, 1H), 4.19 (d, JHH = 15.3 Hz, 1H), 5.37 (d, JHH = 15.3 Hz, 1H), 6.53 (d, JHH = 7.2 Hz, 2H), 7.11−7.20 (m, 3H), 7.38−7.41 (m, 3H), 7.46−7.50 (m, 2H). 13 C NMR (100 MHz, CDCl3): δ 24.8, 25.7, 26.0, 26.2, 28.8, 29.7, 30.2, 39.1, 39.3, 46.4, 50.7, 57.5, 65.8, 127.4, 127.7, 127.8, 128.4, 128.5, 128.6, 129.0, 133.6, 144.8, 153.0. IR (ZnSe): 694, 759, 1446, 2920 cm−1. HRMS (ESI): calcd for C26H34N5 [M + H]+ 416.2814, found 416.2812. Rel (S)-1-[(S)-(1-Benzyl-1H-tetrazol-5-yl)(phenyl)methyl]-2-phenylpiperidine (4y). White solid, 64 mg, 78%. Mp: 133−135 °C. 1H NMR (400 MHz, CDCl3): δ 1.38−1.48 (m, 2H), 1.57−1.68 (m, 2H), 1.72−1.76 (m, 2H), 2.88 (d, JHH = 10.8 Hz, 1H), 3.14−3.20 (m, 1H), 3.33 (dd, JHH = 2.5 Hz, JHH = 8.2 Hz, 1H), 3.86 (d, JHH = 15.3 Hz, 1H), 5.13 (d, JHH = 15.3 Hz, 1H), 5.31 (s, 1H), 6.47 (d, JHH = 7.4 Hz, 2H), 6.83 (d, JHH = 6.7 Hz, 2H), 6.90 (t, JHH = 7.5 Hz, 2H), 6.99 (t, JHH = 7.3 Hz, 1H), 7.07−7.15 (m, 3H), 7.27−7.31 (m, 2H), 7.36 (t, JHH = 7.2 Hz, 1H), 7.43 (t, JHH = 7.2 Hz, 2H). 13C NMR (100 MHz, CDCl3): δ 25.0, 26.3, 37.3, 46.8, 50.9, 57.3, 65.9, 127.4, 127.5, 127.6, 127.7, 128.0, 128.3, 120.4, 128.5, 129.2, 132.4, 136.3, 144.1, 152.7. IR (ZnSe): 694, 1452, 1492, 2850, 2931 cm−1. HRMS (ESI): calcd for C26H28N5 [M + H]+ 410.2339, found 410.2342. Rel (S)-1-[(S)-(1-Benzyl-1H-tetrazol-5-yl)(4-methoxyphenyl)methyl]-2-phenylpiperidine (4z). White solid, 56 mg, 64%. Mp: 105−107 °C. 1H NMR (400 MHz, CDCl3): δ 1.37−1.47 (m, 2H), 1.56−1.64 (m, 2H), 1.73 (d, JHH = 12.7 Hz, 2H), 2.90 (d, JHH = 11.1 Hz, 1H), 3.16 (t, JHH = 11.4 Hz, 1H), 3.32−3.35 (m, 1H), 3.73 (s, 3H), 3.89 (d, JHH = 15.3 Hz, 1H), 5.08 (d, JHH = 15.3 Hz, 1H), 5.24 (s, 1H), 6.48 (d, JHH = 7.4 Hz, 2H), 6.63 (d, JHH = 8.7 Hz, 2H), 6.75 (d, JHH = 8.5 Hz, 2H), 6.93 (t, JHH = 7.4 Hz, 2H), 7.01 (t, JHH = 7.4 Hz, 1H), 7.27 (bs, 2H), 7.34 (t, JHH = 7.2 Hz, 1H), 7.41 (t, JHH = 7.1 Hz, 2H). 13C NMR (100 MHz, CDCl3): δ 25.1, 26.3, 37.4, 46.5, 50.8, 55.2, 56.8, 65,8, 113.5, 127.5, 127.6, 127.7, 128.3, 129.1, 129.8, 132.5, 144.1,152.9, 158.9. IR (ZnSe): 704, 1250, 1512, 2850, 2932 cm−1. HRMS (ESI): calcd for C27H30N5O [M + H]+ 440.2450, found 440.2446. Rel (S)-1-[(S)-(1-Benzyl-1H-tetrazol-5-yl)(4-nitrophenyl)methyl]-2phenylpiperidine (4aa). Yellow oil, 56 mg, 62%. 1H NMR (400 MHz, CDCl3): δ 1.37−1.47 (m, 2H), 1.61−1.69 (m, 2H), 1.78 (d, JHH = 10.0 Hz, 2H), 2.76 (d, JHH = 11.6 Hz, 1H), 3.12 (t, JHH = 11.3 Hz, 1H), 3.23 (d, JHH = 9.3 Hz, 1H), 3.73 (d, JHH = 15.4 Hz, 1H), 5.36 (s,

Rel (S)-1-[(S)-1-(1-Benzyl-1H-tetrazol-5-yl)-2-methylpropyl]-2(methoxymethyl)piperidine (4p). White solid, 52 mg, 76%. Mp: 103−105 °C. 1H NMR (400 MHz, CDCl3): δ 0.33 (d, JHH = 6.9 Hz, 3H), 1.04 (d, JHH = 6.9 Hz, 3H), 1.08−1.34 (m, 3H), 1.49−1.60 (m, 3H), 1.92 (td, JHH = 2.6 Hz, JHH = 12.1 Hz, 1H), 2.36−2.47 (m, 2H), 3.11 (dt, JHH = 3.1 Hz, JHH = 12.4 Hz, 1H), 3.28−3.31 (s+m, 4H), 3.52−3.56 (m, 1H), 4.20 (d, JHH = 10.66 Hz, 1H), 5.66 (d, JHH = 15.1 Hz, 1H), 5.93 (d, JHH = 15.1 Hz, 1H), 7.17−7.32 (m, 5H). 13C NMR (100 MHz, CDCl3): δ 19.8, 20.7, 23.6, 25.8, 29.9, 31.1, 47.4, 50.0, 58.0, 58.6, 59.6, 79.3, 127.4, 128.3, 128.7, 134.8, 154.0. IR (ZnSe): 728, 1097, 1446, 2931 cm−1. HRMS (ESI): calcd for C19H30N5O [M + H]+ 344.2445, found 344.2448. Rel (S)-1-[(S)-1-(1-Benzyl-1H-tetrazol-5-yl)-2-methylpropyl]-2phenylpiperidine (4q). White solid, 68 mg, 90%, Mp: 138−140 °C. 1 H NMR (400 MHz, CDCl3): δ −0.33 (d, JHH = 6.7 Hz, 3H), 1.09 (d, JHH = 6.7 Hz, 3H), 1.18−1.29 (m, 1H), 1.41−1.62 (m, 2H), 1.68−1.78 (m, 3H), 2.32−2.42 (m, 1H), 2.51 (dt, JHH = 2.1 Hz, JHH = 10.0 Hz, 1H), 2.94 (dd, JHH = 2.6 Hz, JHH = 8.1 Hz, 1H), 3.32−3.35 (m, 1H), 3.70 (d, JHH = 10.7 Hz, 1H), 4.22 (d, JHH = 15.3 Hz, 1H), 5.40 (d, JHH = 15.3 Hz, 1H), 6.54 (d, JHH = 7.2 Hz, 2H), 7.12−7.21 (m, 3H), 7.39− 7.51 (m, 5H). 13C NMR (100 MHz, CDCl3): δ 19.0, 19.8, 24.9, 26.0, 30.0, 39.3, 46.4, 50.7, 58.4, 65.9, 127.5, 127.8, 127.9, 128.6, 128.7, 129.1, 133.7, 144.9, 153.3. IR (ZnSe): 701, 716, 1451, 2935 cm−1. HRMS (ESI): calcd for C23H30N5 [M + H]+ 376.2496, found 376.2502. Rel (S)-1-[(S)-1-(1-Benzyl-1H-tetrazol-5-yl)-2-methylpropyl]-2phenylazepane (4r). White solid, 65 mg, 83%. Mp: 92−94 °C. 1H NMR (400 MHz, CDCl3): δ −0.31 (d, JHH = 6.7 Hz, 3H), 1.10 (d, JHH = 6.7 Hz, 3H), 1.19−1.26 (m, 1H), 1.56−1.86 (m, 7H), 2.33−2.37 (m, 1H), 2.59 (dd, JHH = 3.9 Hz, JHH = 10.9 Hz, 1H), 3.41 (d, JHH = 10.7 Hz, 1H), 3.48−3.52 (m, 2H), 4.87 (d, JHH = 15.1 Hz, 1H), 5.65 (d, JHH = 15.1 Hz, 1H), 6.55 (d, JHH = 7.3 Hz, 2H), 7.11−7.23 (m, 3H), 7.35− 7.52 (m, 5H). 13C NMR (100 MHz, CDCl3): δ 18.9, 20.4, 21.5, 29.1, 31.3, 31.5, 36.9, 44.7, 50.7, 60.3, 66.0, 127.1, 127.8, 128.1, 128.6, 128.6, 128.7, 133.6, 145.2, 154.8. IR (ZnSe): 696, 725, 1452, 2927 cm−1. HRMS (ESI): calcd for C24H32N5 [M + H]+ 390.2658, found 390.2654. Rel (S)-1-[(S)-1-(1-Benzyl-1H-tetrazol-5-yl)-2-methylpropyl]-2-cyclohexylazepane (4s). White solid, 62 mg, 79%. Mp: 128−130 °C. 1H NMR (400 MHz, CDCl3): δ 0.23 (d, JHH = 6.6 Hz, 3H), 0.66−0.75 (m, 1H), 0.89−0.96 (m, 1H), 0.99 (d, JHH = 6.6 Hz, 3H), 1.08−1.38 (m, 10H), 1.50−1.57 (m, 2H), 1.62−1.72 (m, 3H), 1.75−1.85 (m, 2H), 2.18−2.22 (m, 1H), 2.42−2.47 (m, 1H), 2.96 (dd, JHH = 5.1 Hz, JHH = 9.3 Hz, 1H), 3.15 (q, JHH = 7.1 Hz, 1H), 3.53 (d, JHH = 10.5 Hz, 1H), 5.44 (d, JHH = 15.6 Hz, 1H), 5.70 (d, JHH = 15.6 Hz, 1H), 7.17− 7.21 (m, 2H), 7.32−7.37 (m, 3H). 13C NMR (100 MHz, CDCl3): δ 19.7, 20.1, 26.2, 26.6, 26.8, 26.9, 27.1, 28.3, 28.4, 29.7, 30.5, 31.2, 42.9, 45.7, 51.2, 62.4, 67.8, 127.5, 128.9, 129.1, 133.9, 156.1. IR (ZnSe): 704, 1450, 2854, 2927 cm−1. HRMS (ESI): calcd for C24H38N5 [M + H]+ 396.3127, found 396.3121. Rel (S)-1-[(S)-1-(1-Benzyl-1H-tetrazol-5-yl)-2-methylpropyl]-2-isobutylazepane (4t). White solid, 61 mg, 82%. Mp: 125−127 °C. 1H NMR (400 MHz, CDCl3): δ 0.22 (d, JHH = 6.6 Hz, 3H), 0.74−0.78 (m, 1H), 0.83 (dd, JHH = 1.8 Hz, JHH = 6.6 Hz, 6H), 1.04 (d, JHH = 6.6 Hz, 3H), 1.25−1.55 (m, 9H), 1.64−1.71 (m, 1H), 2.31−2.40 (m, 1H), 2.83−2.89 (m, 1H), 3.01−3.15 (m, 2H), 3.52 (d, JHH = 10.0 Hz, 1H), 5.40 (d, JHH = 15.4 Hz, 1H), 5.77 (d, JHH = 15.4 Hz, 1H), 7.22−7.24 (m, 2H), 7.34−7.36 (m, 3H). 13C NMR (100 MHz, CDCl3): δ 19.6, 20.5, 21.8, 23.3, 23.4, 24.9, 29.0, 29.3, 30.5, 30.7, 42.6, 45.8, 51.0, 57.8, 62.5, 127.5, 128.9, 129.1, 138.5, 155.3. IR (ZnSe): 694, 717, 1086, 1456, 2929 cm−1. HRMS (ESI): calcd for C22H36N5 [M + H]+ 370.2971, found 370.2967. Rel (S)-1-[(S)-1-(1-Benzyl-1H-tetrazol-5-yl)-2-methylpropyl]-2hexylazepane (4u). White solid, 67 mg, 84%. Mp: 79−81 °C. 1H NMR (400 MHz, CDCl3): δ 0.24 (d, JHH = 6.7 Hz, 3H), 0.87 (t, JHH = 7.1 Hz, 3H), 0.91−0.98 (m, 2H), 1.06 (d, JHH = 6.7 Hz, 3H), 1.12− 1.55 (m, 15H), 1.65−1.72 (m, 1H), 2.31−2.36 (m, 1H), 2.79−2.86 (m, 1H), 2.92−2.98 (m, 1H), 3.06−3.11 (m, 1H), 3.52 (d, JHH = 10.1 Hz, 1H), 5.40 (d, JHH = 15.4 Hz, 1H), 5.71 (d, JHH = 15.4 Hz, 1H), 7.24−7.26 (m, 2H), 7.34−7.39 (m, 3H). 13C NMR (100 MHz, 6105

DOI: 10.1021/acs.joc.7b00611 J. Org. Chem. 2017, 82, 6100−6107

Article

The Journal of Organic Chemistry

7.13 (m, 2H), 7.39 (d, JHH = 7.4 Hz, 1H), 7.39 (t, JHH = 7.6 Hz, 1H). 13 C NMR (100 MHz, CDCl3): δ 17.9, 19.1, 20.6, 20.8, 24.8, 26.1, 30.5, 37.5, 48.3, 58.8, 65.6, 126.8, 127.6, 127.8, 129.3, 129.5, 130.6, 133.2, 135.1, 136.8, 143.3, 155.8. IR (ZnSe): 538, 708, 1469, 2942 cm−1. HRMS (ESI): calcd for C24H32N5 [M + H]+ 390.2652, found 390.2659. 3-[(S)-1-((S)-2-Methyl-1-{1-[(S)-1-(4-methyl-2,6,7-trioxabicyclo[2.2.2]octan-1-yl)ethyl]-1H-tetrazol-5-yl}propyl)piperidin-2-yl]pyridine (4ah). Yellow oil, 57 mg, 65%. 1H NMR (400 MHz, CDCl3): δ 0.29 (d, JHH = 6.7 Hz, 3H), 0.84 (s, 3H), 1.11 (d, JHH = 6.7 Hz, 3H), 1.14−1.21 (m, 1H), 1.32 (d, JHH = 7.0 Hz, 3H), 1.38−1.45 (m, 1H), 1.50−1.73 (m, 4H), 2.36−2.52 (m, 2H), 3.24 (d, JHH = 10.6 Hz, 1H), 3.31−3.36 (m, 2H), 3.86 (q, JHH = 6.9 Hz, 1H), 3.99 (s, 6H), 7.25− 7.28 (m, 1H), 7.78−7.84 (m, 1H), 8.52 (dd, JHH = 1.4 Hz, JHH = 3.3 Hz, 1H), 8.62 (d, JHH = 1.6 Hz, 1H). 13C NMR (100 MHz, CDCl3): δ 14.1, 16.6, 20.2, 24.4, 25.9, 30.7, 31.0, 38.9, 46.9, 56.8, 59.7, 61.6, 72.7, 107.2, 123.3, 135.5, 140.5, 148.6, 149.8, 153.5. IR (ZnSe): 721, 1001, 1091, 1265, 1464, 2933 cm−1. HRMS (ESI): calcd for C23H35N6O3 [M + H]+ 443.2765, found 443.2767. [α]20D = −185.6° (c 0.85, CH2Cl2). Rel (S)-1-[(S)-1-(1-Cyclohexyl-1H-tetrazol-5-yl)-2-methylpropyl]2-phenylpiperidine (4ai). White solid, 64 mg, 87%. Mp: 138−140 °C. 1H NMR (400 MHz, CDCl3): δ 0.44 (d, JHH = 6.6 Hz, 3H), 0.79− 0.89 (m, 1H), 1.13−1.22 (m, 3H), 1.25 (d, JHH = 6.6 Hz, 3H), 1.38− 1.68 (m, 8H), 1.73−1.78 (m, 1H), 1.87−1.95 (m, 2H), 2.19−2.29 (m, 1H), 2.46−2.58 (m, 2H), 2.87 (dd, JHH = 2.5 Hz, JHH = 8.2 Hz, 1H), 3.15−3.22 (m, 1H), 3.37 (d, JHH = 12.3 Hz, 1H), 3.64 (d, JHH = 10.7 Hz, 1H), 7.30−7.39 (m, 5H). 13C NMR (100 MHz, CDCl3): δ 20.0, 20.1, 24.6, 24.7, 24.8, 25.0, 26.0, 30.4, 32.3, 34.4, 39.4, 46.5, 56.5, 58.8, 65.6, 127.1, 127.2, 128.8, 144.9, 152.1. IR (ZnSe): 706, 750, 1095, 1450, 2935 cm−1. HRMS (ESI): calcd for C22H34N5 [M + H]+ 368.2809, found 368.2811. General Procedure for Debenzylation. The solution of the appropriate tetrazole (4a, 4c, or 4m) (1 mmol) in 10 mL of MeOH was treated with 10% palladium on carbon (5 mol %) and placed under hydrogen (20 atm). Stirring was continued at room temperature for a few hours (TLC control), after which the mixture was filtered through Celite, washed with methanol, and concentrated to give the product (5a−c). (S)-Methyl 1-[(S)-2-Methyl-1-(1H-tetrazol-5-yl)propyl]pyrrolidine2-carboxylate (5a). Pink oil, 199 mg, 79%. 1H NMR (400 MHz, CDCl3): δ 0.73 (d, JHH = 6.5 Hz, 3H), 1.14 (d, JHH = 6.5 Hz, 3H), 1.59−1.65 (m, 1H), 1.79−1.95 (m, 3H), 2.42−2.48 (m, 1H), 2.88− 2.94 (m, 1H), 3.22−3.27 (m, 1H), 3.48 (t, JHH = 7.1 Hz, 1H), 3.66 (s, 3H), 4.29 (d, JHH = 9.7 Hz, 1H), 13.47 (bs, 1H). 13C NMR (100 MHz, CDCl3): δ 19.4, 19.9, 23.5, 28.9, 30.2, 47.8, 52.2, 62.1, 62.7, 154.8, 173.9. IR (ZnSe): 1173, 1200, 1436, 1736, 2960, 3101 cm−1. HRMS (ESI): calcd for C11H20N5O2 [M + H]+ 254.1612, found 254.1612. [α]20D = −78.5° (c 0.78, CH2Cl2). {(S)-1-[(S)-2-Methyl-1-(1H-tetrazol-5-yl)propyl]pyrrolidin-2-yl}diphenylmethanol (5b). White solid, 331 mg, 88%. Mp: 133−135 °C. 1 H NMR (400 MHz, CDCl3): δ 0.42 (d, JHH = 6.5 Hz, 3H), 0.88 (d, JHH = 6.5 Hz, 3H), 0.96−1.01 (m, 1H), 1.53−1.63 (m, 2H), 1.75−1.82 (m, 1H), 2.41−2.47 (m, 1H), 3.23−3.45 (m, 3H), 4.82 (bs, 1H), 7.14−7.25 (m, 4H), 7.35 (t, JHH = 7.6 Hz, 2H), 7.56 (d, JHH = 7.6 Hz, 2H), 7.85 (d, JHH = 7.7 Hz, 2H). 13C NMR (100 MHz, CDCl3): δ 19.5, 20.0, 24.6, 28.5, 29.7, 49.5, 64.4, 71.1, 78.7, 125.6, 126.3, 127.0, 127.4, 128.3, 128.6, 144.5, 145.1, 155.3. IR (ZnSe): 702, 746, 1207, 1369, 1448, 2965, 3158, 3388 cm−1. HRMS (ESI): calcd for C22H28N5O [M + H]+ 378.2288, found 378.2289. [α]20D = −83.4° (c 0.67, CH2Cl2). 3-{(S)-1-[(S)-2-Methyl-1-(1H-tetrazol-5-yl)propyl]piperidin-2-yl}pyridine (5c). Yellow solid, 137 g, 48%. Mp: 168−180 °C. 1H NMR (400 MHz, CDCl3): δ 0.53 (d, JHH = 6.4 Hz, 3H), 1.16 (d, JHH = 6.4 Hz, 3H), 1.20−1.23 (m, 1H), 1.37−1.47 (m, 1H), 1.57−1.78 (m, 4H), 2.49−2.57 (m, 2H), 2.97 (dd, JHH = 2.3 Hz, JHH = 8.4 Hz, 1H), 3.33 (d, JHH = 11.7 Hz, 1H), 3.57 (d, JHH = 11.0 Hz, 1H), 7.34 (dd, JHH = 2.9 Hz, JHH = 4.9 Hz, 1H), 7.84 (d, JHH = 4.0 Hz, 1H), 7.99 (d, JHH = 7.8 Hz, 1H), 8.37 (s, 1H). 13C NMR (100 MHz, CDCl3): δ 19.9, 20.6, 24.5, 25.8, 28.9, 38.1, 46.1, 61.1, 62.7, 124.5, 137.1, 141.5, 145.8, 147.3, 153.9. IR (ZnSe): 714, 729, 1427, 2931, 3097 cm−1. HRMS (ESI):

1H), 5.42 (d, JHH = 15.4 Hz, 1H), 6.41 (d, JHH = 7.3 Hz, 2H), 6.85− 6.95 (m, 5H), 7.33 (bs, 2H), 7.42−7.46 (m, 1H), 7.50−7.53 (m, 2H), 7.88 (d, JHH = 8.7 Hz, 2H). 13C NMR (100 MHz, CDCl3): δ 24.9, 26.1, 37.3, 47.4, 51.2, 56.7, 66.1, 123.0, 127.4, 127.5, 128.1, 128.6, 129.0, 129.5, 132.4, 143.7, 147.0, 151.8. IR (ZnSe): 700, 1348, 1520, 2933 cm−1. HRMS (ESI): calcd for C26H27N6O2 [M + H]+ 455.2195, found 455.2193. Rel (R)-2-(1-Benzyl-1H-tetrazol-5-yl)-2-[(S)-2-phenylpiperidin-1yl]ethanol (4ab). White solid, 50 mg, 69%. Mp: 135−137 °C. 1H NMR (400 MHz, CDCl3): δ 1.32−1.39 (m, 1H), 1.53−1.65 (m, 2H), 1.76−1.84 (m, 3H), 2.71−2.77 (m, 2H), 2.92 (bs, 1H), 3.19 (d, JHH = 2.0 Hz, JHH = 8.8 Hz, 1H), 3.37 (bd, JHH = 11.9 Hz, 1H), 3.80 (d, JHH = 10.3 Hz, 1H), 4.26 (d, JHH = 15.3 Hz, 1H), 4.29−4.33 (m, 1H), 5.47 (d, JHH = 15.3 Hz, 1H), 6.58 (d, JHH = 7.0 Hz, 2H), 7.08−7.48 (8H, m, Ar). 13C NMR (100 MHz, CDCl3): δ 24.8, 26.2, 37.9, 47.1, 50.8, 53.5, 59.5, 66.3, 127.2, 127.6, 127.9, 128.9, 129.0, 129.3, 133.3, 143.1, 151.3. IR (ZnSe): 708, 732, 768, 1053, 1450, 2927, 3350 cm−1. HRMS (ESI): calcd for C21H26N5O [M + H]+ 364.2137, found 364.2136. Rel (S)-1-[(S)-1-(1-tert-Butyl-1H-tetrazol-5-yl)-2-methylpropyl]-2phenylpiperidine (4ac). White solid, 63 mg, 92%. Mp: 149−151 °C. 1 H NMR (400 MHz, CDCl3): δ 0.57 (d, JHH = 6.6 Hz, 3H), 1.18 (s, 9H), 1.23 (d, J = 6.6, 3H), 1.30−1.58 (m, 3H), 1.64−1.66 (m, 2H), 1.76−1.78 (m, 1H), 2.35−2.47 (m, 1H), 2.97−3.09 (m, 2H), 3.42 (d, J = 12.0, 1H), 4.20 (d, JHH = 10.6 Hz, 1H), 7.23−7.32 (m, 5H). 13C NMR (100 MHz, CDCl3): δ 20.3, 20.5, 25.0, 26.4, 30.0, 31.6, 39.8, 46.4, 59.6, 63.1, 65.3, 127.2, 127.6, 128.9, 145.3, 154.1. IR (ZnSe): 708, 760, 1097, 1450, 2854, 2931 cm−1. HRMS (ESI): calcd for C20H32N5 [M + H]+ 342.2658, found 342.2654. Rel Ethyl 2-(5-{(S)-2-Methyl-1-[(S)-2-phenylpiperidin-1-yl]propyl}1H-tetrazol-1-yl)acetate (4ad). Brown oil, 65 mg, 87%. 1H NMR (400 MHz, CDCl3): δ 0.43 (d, JHH = 6.5 Hz, 3H), 1.17−1.24 (m, 6H), 1.26−1.76 (m, 6H), 2.43−2.48 (m, 1H), 2.59 (t, JHH = 12.1 Hz, 1H), 2.76−2.79 (m, 1H), 3.33 (d, JHH = 11.8 Hz, 1H), 3.52 (d, JHH = 10.7 Hz, 1H), 3.78 (d, JHH = 17.6 Hz, 1H), 4.08 (q, JHH = 7.1 Hz, 2H), 4.52 (d, JHH = 17.6 Hz, 1H), 7.22−7.38 (m, 5H). 13C NMR (100 MHz, CDCl3): δ 13.8, 19.9, 20.1, 24.8, 26.0, 30.1, 38.7, 46.3, 47.4, 58.9, 62.4, 65.9, 127.6, 129.0, 144.0, 154.0, 165.0. IR (ZnSe): 706, 760, 1207, 1446, 1753, 2933 cm−1. HRMS (ESI): calcd for C20H30N5O2 [M + H]+ 372.2400, found 372.2405. Rel (S)-1-[(S)-1-(1-Allyl-1H-tetrazol-5-yl)-2-methylpropyl]-2-phenylpiperidine (4ae). White solid, 54 mg, 83%. Mp: 95−97 °C. 1H NMR (400 MHz, CDCl3): δ 0.40 (d, JHH = 6.7 Hz, 3H), 1.20 (d, JHH = 6.7 Hz, 3H), 1.24−1.28 (m, 1H), 1.57−1.78 (m, 5H), 2.44−2.50 (m, 1H), 2.63−2.67 (m, 1H), 2.84 (d, JHH = 9.8 Hz, 1H), 3.37 (d, JHH = 11.5 Hz, 1H), 3.69 (dd, JHH = 7.0 Hz, JHH = 8.8 Hz, 2H), 4.44 (d, JHH = 13.5 Hz, 1H), 4.69 (d, JHH = 17.0 Hz, 1H), 5.08 (d, JHH = 10.2 Hz, 1H), 5.59−5.63 (m, 1H), 7.22−7.40 (m, 5H). 13C NMR (100 MHz, CDCl3): δ 20.0, 20.7, 24.8, 26.0, 30.3, 38.8, 46.5, 49.5, 58.8, 66.1,120.2, 127.5, 127.7, 128.9, 130.6, 144.2, 153.6. IR (ZnSe): 705, 759, 1450, 2937 cm−1. HRMS (ESI): calcd for C19H28N5 [M + H]+ 326.2345, found 326.2340. Rel 3-[2-(5-{(S)-2-Methyl-1-[(S)-2-phenylpiperidin-1-yl]propyl}1H-tetrazol-1-yl)ethyl]-1H-indole (4af). White solid, 56 mg, 65%. Mp: 209−211 °C. 1H NMR (400 MHz, CDCl3): δ −0.07 (d, JHH = 6.6 Hz, 3H), 1.09 (d, JHH = 6.6 Hz, 3H), 1.17−1.27 (m, 1H), 1.39−1.74 (m, 5H), 2.35−2.47 (m, 2H), 2.84 (dd, JHH = 2.4 Hz, JHH = 8.3 Hz, 1H), 3.19−3.31 (m, 3H), 3.50 (d, JHH = 10.7 Hz, 1H), 3.60−3.68 (m, 1H), 4.02−4.09 (m, 1H), 6.68 (d, JHH = 1.5 Hz, 1H), 7.01−7.08 (m, 2H), 7.17 (t, JHH = 7.8 Hz, 1H), 7.24−7.35 (m, 6H), 8.31 (bs, 1H). 13 C NMR (100 MHz, CDCl3): δ 19.2, 19.8, 24.8, 25.7, 26.0, 29.7, 38.9, 46.4, 47.3, 58.6, 65.8, 110.1, 111.2, 117.9, 119.5, 122.1, 122.4, 126.5, 127.3, 127.6, 128.8, 136.2, 144.4, 153.3. IR (ZnSe): 708, 742, 1457, 2938, 3305 cm−1. HRMS (ESI): calcd for C26H33N6 [M + H]+ 429.2767, found 429.2765. Rel (S)-1-{(S)-2-Methyl-1-[1-(2,6-dimethylphenyl)-1H-tetrazol-5yl]propyl}-2-phenylpiperidine (4ag). Yellow solid, 60 mg, 77%. Mp: 186−188 °C. 1H NMR (400 MHz, CDCl3): δ 0.65 (d, JHH = 6.8 Hz, 3H), 1.01−1.06 (m, 1H), 1.09 (d, JHH = 6.8 Hz, 3H), 1.43−1.57 (m, 3H), 1.64 (s, 3H), 1.65−1.76 (m, 3H), 2.21 (s, 3H), 2.80−2.89 (m, 2H), 3.31 (m, 2H), 6.33 (bs, 2H), 6.99 (t, JHH = 7.6 Hz, 2H), 7.06− 6106

DOI: 10.1021/acs.joc.7b00611 J. Org. Chem. 2017, 82, 6100−6107

Article

The Journal of Organic Chemistry calcd for C15H23N6 [M + H]+ 287.1979, found 287.1980. [α]20D = −94.6° (c 0.52, CH2Cl2).

■

(6) Ramon, D. J.; Yus, M. Angew. Chem., Int. Ed. 2005, 44, 1602− 1634. (7) Nenajdenko, V. G.; Reznichenko, A. L.; Balenkova, E. S. Tetrahedron 2007, 63, 3031. (8) Tron, G. C. Eur. J. Org. Chem. 2013, 2013, 1849−1859. (9) Basso, A.; Banfi, L.; Guanti, G.; Riva, R. Org. Biomol. Chem. 2009, 7, 253−258. (10) (a) Belding, L.; Zaretsky, S.; Rotstein, B. R.; Yudin, A. K.; Dudding, T. J. Org. Chem. 2014, 79, 9465−9471. (b) Hili, R.; Rai, V.; Yudin, A. K. J. Am. Chem. Soc. 2010, 132, 2889. (11) (a) Lv, F.; Li, Z.-F.; Hu, W.; Wu, X. Bioorg. Med. Chem. 2015, 23, 7661−7670. (b) Chauhan, K.; Singh, P.; Kumar, V.; Shukla, P. K.; Siddiqi, M. I.; Chauhan, P. M. S. Eur. J. Med. Chem. 2014, 78, 442− 454. (c) Kambe, T.; Correia, B. E.; Niphakis, M. J.; Cravatt, B. F. J. Am. Chem. Soc. 2014, 136, 10777−10782. (12) (a) Bavetsias, V.; Marriott, J. H.; Melin, C.; Kimbell, R.; Matusiak, Z. S.; Boyle, F. T.; Jackman, A. L. J. Med. Chem. 2000, 43, 1910−1926. (b) Upadhayaya, R. S.; Jain, S.; Sinha, N.; Kishore, N.; Chandra, R.; Arora, S. K. Eur. J. Med. Chem. 2004, 39, 579−592. (c) Ostrovskii, V. A.; Trifonov, R. E.; Popova, E. A. Russ. Chem. Bull. 2012, 61, 768−780. (13) Gao, H.; Shreeve, J. M. Chem. Rev. 2011, 111, 7377−7436. (14) (a) Longbottom, D. A.; Franckevičius, V.; Ley, S. V. Chimia 2007, 61, 247−256. (b) Bhanushali, M.; Zhao, C.-G. Synthesis 2011, 2011, 1815−1830. (c) Doyle, A. G.; Jacobsen, E. N. Chem. Rev. 2007, 107, 5713−5743. (15) (a) Popova, E. A.; Trifonov, R. E.; Ostrovskii, V. A. ARKIVOC 2012, 2012, 45−65. (b) Aromí, G.; Barrios, L. A.; Roubeau, O.; Gamez, P. Coord. Chem. Rev. 2011, 255, 485−546. (16) Shmatova, O. I.; Nenajdenko, V. G. J. Org. Chem. 2013, 78, 9214−9222. (17) Gabrielsen, M.; Kurczab, R.; Ravna, A. W.; Kufareva, I.; Abagyan, R.; Chilmonczyk, Z.; Bojarski, A. J.; Sylte, I. Eur. J. Med. Chem. 2012, 47, 24−37. (18) Lipinski, C. A.; Lombardo, F.; Dominy, B. W.; Feeney, P. J. Adv. Drug Delivery Rev. 2001, 46, 3−26. (19) Hoffman, R. V. Organic Chemistry: An Intermediate Text, 2nd ed.; John Wiley and Sons, Inc.: Hoboken, NJ, 2004. (20) Zhdanko, A. G.; Nenajdenko, V. G. J. Org. Chem. 2009, 74, 884−887.

ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.7b00611. General information and spectral data (PDF)

■

AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Valentine G. Nenajdenko: 0000-0001-9162-5169 Notes

The authors declare no competing financial interest.

■

ACKNOWLEDGMENTS This study was supported by the Ministry of Education and Science of the Russian Federation (Agreement 02.a03.21.0008). We thank N. G. Voznesenskaya for NMR spectra, Prof. Y. V. Zubavichus and P. V. Dorovatovskii for obtaining the synchrotron X-ray experimental data (NRC “Kurchatov Institute”), and Dr. O. I. Shmatova, Dr. V. M. Muzalevskiy, I. V. Kutovaya, A. M. Kabylda, and I. V. Smolyar for helpful discussion.

■

REFERENCES

(1) (a) Nenajdenko, V. G. Isocyanide Chemistry: Applications in Synthesis and Material Science; Wiley-VCH: Weinheim, Germany, 2012. (b) Zhu, J.; Wang, Q.; Wang, M.-X. Multicomponent Reactions in Organic Synthesis; Wiley-VCH: Weinheim, Germany, 2015. (c) Dömling, A. Chem. Rev. 2006, 106, 17−89. (d) Dömling, A.; Ugi, I. Angew. Chem., Int. Ed. 2000, 39, 3168−3210. (e) Gulevich, A. V.; Zhdanko, A. G.; Orru, R. V. A.; Nenajdenko, V. G. Chem. Rev. 2010, 110, 5235− 5331. (2) (a) Yue, T.; Wang, M.-X.; Wang, D.-X.; Masson, G.; Zhu, J. Angew. Chem., Int. Ed. 2009, 48, 6717−6721. (b) Su, Y.; Bouma, M. J.; Alcaraz, L.; Stocks, M.; Furber, M.; Masson, G.; Zhu, J. Chem. - Eur. J. 2012, 18, 12624−12627. (c) Hashimoto, T.; Kimura, H.; Kawamata, Y.; Maruoka, K. Angew. Chem. 2012, 124, 7391−7393. (d) Zhao, W.; Huang, L.; Guan, Y.; Wulff, W. D. Angew. Chem., Int. Ed. 2014, 53, 3436−3441. (e) Zhang, Y.; Ao, Y.-F.; Huang, Z.-T.; Wang, D.-X.; Wang, M.-X.; Zhu, J. Angew. Chem., Int. Ed. 2016, 55, 5282−5285. (3) (a) Denmark, S. E.; Fan, Y. J. Am. Chem. Soc. 2003, 125, 7825− 7827. (b) Kusebauch, U.; Beck, B.; Messer, K.; Herdtweck, E.; Dömling, A. Org. Lett. 2003, 5, 4021−4024. (c) Andreana, P. R.; Liu, C. C.; Schreiber, S. L. Org. Lett. 2004, 6, 4231−4233. (4) (a) Ross, G. F.; Herdtweck, E.; Ugi, I. Tetrahedron 2002, 58, 6127. (b) Hebach, C.; Kazmaier, U. Chem. Commun. 2003, 596−597. (c) Nenajdenko, V. G.; Gulevich, A. V.; Chernichenko, K. Yu.; Sokolova, N. V.; Balenkova, E. S. Mendeleev Commun. 2011, 21, 245− 246. (d) Basso, A.; Banfi, L.; Riva, R.; Guanti, G. J. Org. Chem. 2005, 70, 575−579. (e) Banfi, L.; Basso, A.; Chiappe, C.; De Moliner, F.; Riva, R.; Sonaglia, L. Org. Biomol. Chem. 2012, 10, 3819−3829. (f) Linderman, R. J.; Binet, S.; Petrich, S. R. J. Org. Chem. 1999, 64, 336. (g) Kunz, H.; Pfrengle, W. Tetrahedron 1988, 44, 5487. (5) (a) Banfi, L.; Basso, A.; Cerulli, V.; Rocca, V.; Riva, R. Beilstein J. Org. Chem. 2011, 7, 976−979. (b) Znabet, A.; Ruijter, E.; de Kanter, F. J. J.; Köhler, V.; Helliwell, M.; Turner, N. J.; Orru, R. V. A. Angew. Chem., Int. Ed. 2010, 49, 5289−5292. (c) Chapman, T. M.; Davies, I. G.; Gu, B.; Block, T. M.; Scopes, D. I. C.; Hay, P. A.; Courtney, S. M.; McNeill, L. A.; Schofield, C. J.; Davis, B. G. J. Am. Chem. Soc. 2005, 127, 506−507. 6107

DOI: 10.1021/acs.joc.7b00611 J. Org. Chem. 2017, 82, 6100−6107