Substrate-Controlled Chemoselective Reactions of Isocyanoacetates

Aug 29, 2017 - Versatile and chemoselective C–C bond forming methods for the one-pot transformation of amides into other classes of compounds are hi...
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Substrate-Controlled Chemoselective Reactions of Isocyanoacetates with Amides and Lactams Jian-Feng Zheng, Xiu-Ning Hu, Zhen Xu, Dong-Cheng Cai, Tai-Long Shen, and Pei-Qiang Huang* Department of Chemistry, Fujian Provincial Key Laboratory of Chemical Biology, iChEM (Collaborative Innovation Center of Chemistry for Energy Materials), College of Chemistry and Chemical Engineering, Xiamen University, Xiamen, Fujian 361005, P. R. China S Supporting Information *

ABSTRACT: Versatile and chemoselective C−C bond forming methods for the one-pot transformation of amides into other classes of compounds are highly demanding. In this report, we demonstrate the reductive addition of isocyanoacetates to common amides and lactams to produce 5-methoxyoxazoles or bicyclic imidazolines. This one-pot procedure involves partial reduction of amides with Schwartz reagent and chemoselective addition of the carbon of isocyanide group or α-carbon in isocyanoacetates. The quite different reactivity of the isocyanoacetate is due to the different steric hindrance of the amides and lactams.

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INTRODUCTION Since the preparation of the first multifunctional isocyanoacetate in 1961 by Ugi and co-workers,1 isocyanoacetates have become a class of versatile building blocks finding widespread applications in organic synthesis and medicinal chemistry.2 Isocyanoacetates can be easily prepared in three steps from amino acids1 or by aromatic nucleophilic substitution of simple isocyanoacetate,3 and many of them are currently commercially available. An isocyanoacetate containing an α-hydrogen possesses two potential nucleophilic centers: the carbon of the isocyanide group and the α-carbon after deprotonation with a base.4 The nucleophilicity of the isocyanide group of isocyanoacetate was first demonstrated in 1961 by Ugi through the reaction of the isocyanoacetates with in situ-generated imines and acids to give α-acetamidoamides (eq 1 in Scheme 1).5 In 1977, Schö llkopf and co-workers6 reported the nucleophilic addition of α-carbon of isocyanoacetates with imines to provide substituted 2-imidazolines7 (eq 2 in Scheme 1), which is an important class of heterocyclic compounds central to numerous biologically active compounds8 and have been used as catalysts in many reactions.9 After these seminal works, the chemistries of isocyanoacetates have become an area of intensive research. In 2003, Orru and co-workers discovered that by introducing a phenyl group onto the α position of αisocyanoacetate, the three component synthesis of imidazolines can proceed in high yield without the need for premetalation (eq 3 in Scheme 1).10 In 2007, Zhu and co-workers introduced methyl α-(p-nitrophenyl)-α-isocyanoacetate. The strategical incorporation of the nitro group onto the phenyl ring renders the α-C−H bond even more acidic and the conjugate base less nucleophilic, thus allowing the ester carbonyl oxygen to act as a third nucleophilic center to yield 5-methoxyoxazoles (eq 4 in Scheme 1).3,11 Despite these progresses, the electrophilic © 2017 American Chemical Society

Scheme 1. Reported Isocyanoacetates-Based Reactions and Our Plan for the Reductive Coupling of Amides/Lactams with Isocyanoacetates

partners in those reactions are limited to preformed and in situgenerated imines except for two cases where N,N-dimethylforReceived: July 14, 2017 Published: August 29, 2017 9693

DOI: 10.1021/acs.joc.7b01768 J. Org. Chem. 2017, 82, 9693−9703

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The Journal of Organic Chemistry mamide dimethylacetal12 and a carbonitrile13 have been used in the condensations with diamines to give bicyclic imidazoline derivatives. The latter have potential antimicrobial14 and human histamine H4 receptor antagonistic activities13 and have been used as catalysts in catalytic hydrogenation12b and the C−C cross-coupling reactions.15 Very few methods have been reported for their synthesis. Thus, developing other electrophilic partners such as amides in the above-mentioned reactions would extend the scope of those reactions and provide a direct access to bicyclic imidazoline derivatives. As a class of highly stable and easily available compounds,16 amides have found widespread applications in both organic synthesis and medicinal chemistry. Especially in the past decade, the amide group played a pivotal role in enhancing and directing selective C−H functionalization.17 However, because the amide group is fairly inert, synthetically useful methods for the direct transformations of amides are scarce. Breakthroughs in the direct, mild, and chemoselective transformations of amides have been achieved in recent years.18 In 1993, Ganem and co-workers reported the seminal selective reduction of amides with Schwartz reagent (Cp 2 ZrHCl) 19 to give imines.20a,b The method has been extended to the reductive cyanation of secondary lactams20c and deacylation of primary taxanes to prepare paclitaxel20d and the chemoselective reduction of tertiary amides.20e,f Recently, the Chida/Sato group have developed the chemoselective reductive nucleophilic additions of amides with silyl enol ether, allylstannane, or allylzinc reagent to give functionalized amines.21 They reported for the first time the chemoselective reduction of tertiary amides by the Schwartz reagent to give iminium ion intermediates.21a Following these seminal works, the reductive cycloaddition with Danishefsky’s diene and the reductive Ugi− Joullié reaction of hydroxylated secondary lactams were reported.22 Interestingly, Pace and co-workers reported that Schwartz reagent could also be used for the chemoselective reduction of isocyanates to yield formamides.23 On the other hand, by means of activation with triflic anhydride (Tf2O)24 or partial reduction,25 the direct transformation of amides into various heterocyclic compounds has been reported.26 Although many nucleophiles have been employed in the abovementioned and related direct transformations of amides,26 to the best of our knowledge, there have been no report on the reaction of amides with isocyanoacetates. In connection with our recent work on the in situ activation-based direct transformation of amides27 and the reaction of the nitrilium intermediates with isocyanide,28 we report herein the chemoselective reductive coupling of isocyanoacetates with amides and lactams to give 5-methoxyoxazoles and bicyclic imidazolines, respectively (eq 5a,b in Scheme 1).

Table 1. Optimization of the One-Pot Reductive Coupling Reaction of Amide 1a with Isocyanoacetate 3a

conditions (equiv)a

entry 1 2 3 4 5 6 7 8 a b

Cp2ZrHCl Cp2ZrHCl Cp2ZrHCl Cp2ZrHCl Cp2ZrHCl Cp2ZrHCl Cp2ZrHCl Cp2ZrHCl

(1.5), (1.5), (1.5), (1.5), (1.5), (1.5), (1.5), (1.5),

yield (%)b

BF3·OEt2 (1.0), Et3N (1.5) TiCl4 (1.0), Et3N (1.5) ZnCl2 (1.0), Et3N (1.5) TFA (1.0), Et3N (1.5) BF3·OEt2 (1.0) Et3N (1.5) ZnCl2 (0.2), Et3N (1.5) ZnCl2 (0.2), Et3N (2.0)

56 15 80 50 15 72 82 90

Amide (1.0 equiv), isocyanoacetate (1.2 equiv), THF (0.1M). Isolated yield.

spectrum of compound 4a, the Ha appearing at δ 3.58 displayed a diagnostic doublet−doublet split (dd, J = 5.4, 9.4 Hz, 1H), which is in agreement with those of the known one-carbon higher homologue (δ 3.60, dd, J = 5.0, 9.5 Hz, 1H).3 Encouraged by this result, we screened different Lewis acids. Although the use of stronger Lewis acid TiCl4 resulted in a lower yield (15%) (Table 1, entry 2), employment of ZnCl2 led to a significantly improved yield (80%) (Table 1, entry 3). Interestingly, Brønsted acid TFA can also catalyze the reaction to afford the desired product in 50% yield (Table 1, entry 4). On the other hand, controlled experiments were conducted: in the absence of triethylamine, 4a was obtained in only 15% yield (Table 1, entry 5), while in the absence of boron trifluoride etherate the yield of 4a was 72% (Table 1, entry 6). The latter results indicated that Lewis acid is not crucial to the reaction, while triethylamine is essential for the reaction. Indeed, a reduction in the amount of ZnCl2 to 0.2 equiv furnished 4a in 82% yield (Table 1, entry 7), while increasing the amount of triethylamine to 2.0 equiv provided 4a in a further improved yield of 90% (Table 1, entry 8). Thus, optimal reaction conditions were defined as those outlined in entry 8. After optimal conditions were defined, the scope of amide was surveyed. As can be seen from Table 2, tert-amides bearing both primary (n-pentyl, n-nonyl) and secondary (isopropyl, cyclohexyl) alkyl groups underwent reductive 5-methoxyoxazol2-ylation to afford the corresponding oxazoles 4a−d in good yields (86−94%) (Table 2, entries 1−4). However, the reaction of pivalamide 1e resulted in a low yield (35%), which is attributable to the steric hindrance of tert-butyl group in reduction with Cp2ZrHCl (entry 5). Benzamide 1f reacted smoothly to give the corresponding oxazole 4f in 83% yield (entry 6). The reaction tolerated both electron-withdrawing groups such as F, CF3, NO2, and CN (entries 7−10) and electron-donating groups such as Me and OMe (entries 11 and 12) on the benzoyl moiety, affording the corresponding oxazoles (4f−l) in good yields. It is worth noting that the previous method for the synthesis of aryl amino oxazole benzamide derivatives gave only moderate yield.3,11a Encouraged by these results, we next examined the reaction of heteroaromatic amides. To our delight, the reaction worked well with pyridine-3-carboxamide, furan-2-carboxamide, and thiophene-2-carboxamide, furnishing the corresponding oxazoles 4m, 4n, and 4o in 88%, 85%, and 93% yields, respectively

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RESULTS AND DISCUSSION We first investigated the reductive 5-methoxyoxazol-2-ylation of tertiary amides with isocyanoacetates. For this purpose, amide 1a was selected as a model substrate and methyl 2-isocyano-2(4-nitrophenyl)acetate (3a)3 as a nucleophile. Our previous report on the reductive cross-coupling of amides with a ketones29 led us to examine a similar protocol for the current reductive functionalization reaction (Table 1). Thus, tertiary amide 1a was treated with Cp2ZrHCl (1.5 equiv) at rt for 30 min, and then BF3·Et2O (1.0 equiv), isocyanoacetate 3a (1.2 equiv), and triethylamine (1.5 equiv) were added successively. To our delight, after reaction at rt for 2 h, the desired adduct 4a was obtained in 56% yield (Table 1, entry 1). In the 1H NMR 9694

DOI: 10.1021/acs.joc.7b01768 J. Org. Chem. 2017, 82, 9693−9703

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The Journal of Organic Chemistry Table 2. Scope of the One-Pot Reductive Addition of Amides 1 with Isocyanoacetate 3

entry

R1

R2, R3

producta

yield (%)b

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26

n-C5H11 n-C9H19 i-Pr c-C6H11 t-Bu Ph p-FC6H4 p-F3CC6H4 p-O2NC6H4 p-NCC6H4 p-MeC6H4 p-MeOC6H4 3-pyridinyl 2-furanyl 2-thiophenyl n-C5H11 n-C5H11 n-C5H11 n-C5H11 n-C5H11 n-C5H11 n-C5H11 i-Pr c-Hex c-Hex c-Hex

-(CH2)4-(CH2)4-(CH2)4-(CH2)4-(CH2)4-(CH2)4-(CH2)4-(CH2)4-(CH2)4-(CH2)4-(CH2)4-(CH2)4-(CH2)4-(CH2)4-(CH2)4-(CH2)5Et, Et Me, Me Me, Bn Bn, Bn Me, C6H5 -(CH2)4Bn, H Bn, H i-Pr, H c-Hex, H

4a 4b 4c 4d 4e 4f 4g 4h 4i 4j 4k 4l 4m 4n 4o 4p 4q 4r 4s 4t 4u 4v 4w 4x 4y 4z

90 86 94 91 35 83 77 87 67 77 83 83 88 85 93 83 75 75 80 38 26 65 98 80 79 73

Table 3. Scope of the One-Pot Reductive Cycloaddition of Lactams 2 to Isocyanoacetates 3

a c

Ar: p-O2NC6H4 for 5a−i, p-MeO2CC6H4 for 5j. bIsolated yield. Isolated yield of major isomer. dHeated at 40 °C.

(Table 3). The other substituted γ-lactams, such as 4,4dimethyl-2-pyrrolidinone and 5-methyl-2-pyrrolidinone, reacted with isocyanoacetate 3a to give bicyclic imidazolines 5b and 5c in excellent yields (98% and 94%) also (Table 3, entries 2 and 3). Especially when 5-methylpyrrolidin-2-one was employed as a substrate, the desired formal “3 + 2” cycloaddition product imidazoline 5c was obtained as a single diastereomer (94% yield, Table 3, entry 3). The structure of 5c was unambiguously confirmed by single-crystal X-ray diffraction analysis (see Supporting Information). OTBS and ester groups were tolerated under our standard conditions, and the corresponding imidazolines 5d−f were isolated in 71%, 68%, and 66% yield, respectively (Table 3, entries 4−6). Unexpectedly, the reaction of six-membered lactams resulted in low yields or failure to give the corresponding product (Table 3, entries 7−9). Varying the α-aryl substituent on the isocyanoacetates from p-nitrophenyl to p-(methoxycarbonyl)phenyl resulted in a decrease in the yield (Table 3, entry 10). Although we were unable to determine the relative stereochemistries of bicyclic imidazolines 5 by NOESY experiments, the structure of 5c was determined by single crystal X-ray diffraction analysis. Based on the previous reports3,10,11a,21a and our own experimental results, plausible reaction mechanisms for the coupling reactions are depicted in Scheme 2. First, deprotonation of the isocyanoacetate 3 with NEt3 generates carbanion 3A/enolate 3B and triethylaminium ion (Scheme 2, eq 1). On

a

Ar: p-O2NC6H4 for 4a−u, 4w−z; p-MeO2CC6H4 for 4v. bIsolated yield.

(entries 13−15). The scope of N-substituents (entries 16−21) were next surveyed. The amides with cyclic N-alkyl groups (entries 1, 16) outperform acyclic N-alkyl substrates (entries 17−19). Hindered N,N-dibenzylamide and N-methyl-Nphenylamide, being difficult to reduce under standard reaction conditions, only gave lower yields of 38% and 26%, respectively (entries 20 and 21). To further explore the scope of this reaction, the use of other α-isocyanoacetates was investigated. The α-isocyanoacetate bearing a weaker electron-withdrawing group such as 4-(methoxycarbonyl)phenyl produced the desired oxazole 4v in a diminished yield (65%, entry 22). To further reveal the scope of this approach, the reaction of secamide was investigated. To our delight, when Schwartz reagent was slightly increased to 2.2 equiv, the reductive functionalization of secondary amides proceeded smoothly to afford oxazoles (4w−z) in 73−98% yields (entries 23−26). Encouraged by these results, we next turned to secondary lactams. To our surprise, under the conditions used for tertamides, the reaction of 2-pyrrolidinone 2a with isocyanoacetate 3a produced the imidazoline 5a as a separable diastereomeric mixture (combined yield 95%, dr = 3.0:1.0). The characteristic resonances of Ha and Hb in its 1H NMR spectrum which appeared at δ 4.07 (dd, J = 10.1, 6.0 Hz, 1H) and δ 7.04 (s, 1H), respectively, were found in this series of compounds 9695

DOI: 10.1021/acs.joc.7b01768 J. Org. Chem. 2017, 82, 9693−9703

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The Journal of Organic Chemistry

Scheme 3. One-Pot Reductive Addition of sec-Amide 1aa with Isocyanoacetate 3a

Scheme 2. Proposed Mechanisms

isocyanide addition step. Six-membered cyclic imines are less electrophilic than five-membered cyclic imines because the double bond in five-membered rings is more strained. It is worth mentioning that Zr-enolates have been postulated by Ganem20a−c as the primary intermediates in the chemoselective reduction of secondary amides/lactams. Their methods involve either predeprotonation of secondary amides with KH (>1.0 equiv) or with 2 equiv of Schwartz reagent, and hydrogen evolution was observed. In our case, on the basis of the facts that only 1.6 equiv of Schwartz reagent was employed, affording adducts in up to 98% yield, and that no hydrogen evolution was observed, 1C and 2A are plausible primary intermediates.

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CONCLUSIONS We report a one-pot reductive addition reaction of isocyanoacetates with highly stable and easily available tertamides or sec-amides to yield a variety of 5-methoxyoxazoles. In contrast, under the same reaction conditions, the reaction of sec-lactams with isocyanoacetates provided a novel and feasible route for construction of the bicyclic imidazoline skeleton. It is noteworthy that mild conditions, a broad scope of substrates, satisfying yields, and excellent substrate-controlled chemoselectivity were achieved in this reaction. Studies that employ other isocyanides to react with iminium ions generated from amides are currently underway and will be reported in due course.

the other hand, reduction of a tert-amide 1 with Cp2ZrHCl generates complex 1A, which is cleaved by triethylaminium ion and a catalytic amount of ZnCl2 to form iminium ion 1B. Tandem addition of the more nucleophilic isocyanide carbon of nucleophile 3B to iminium ion 1B and capture of the resultant nitrilium intermediate by enolate oxygen ion results in ring closure, thus providing the oxazole 4 (Scheme 2, eq 2A). For secondary amide 1, partial reduction with Cp2ZrHCl generates complex 1C, which is cleaved by triethylaminium ion to form 1D. The latter, being activated by Lewis acid, triethylaminium ion, or ZnCl2, undergoes addition to isocyanide carbon of 3B to form oxazole 4 (Scheme 2, eq 2B). On the other hand, partial reduction of secondary lactam 2 with Cp2ZrHCl generates a cyclic imine 2B which, being sterically less hindered, formed a six-membered chelating structure with ZnCl2 and 3A. The latter undergoes a tandem Mannich-type addition−nucleophilic addition of the resultant nitrogen anion to produce a formal “3 + 2” cycloaddition product, namely bicyclic imidazoline 5 (Scheme 2, eq 3). This speculation is supported by the result obtained from the reaction of sterically less hindered secondary amide 1aa: the reaction of 1aa produced ca. 23% of imidazoline 5aa, along with oxazoline 4aa detectable by NMR monitoring (Scheme 3). Because the reduction of six-membered lactams with Cp2ZrHCl proceeded smoothly as indicated by TLC monitoring, the lower yields observed for the reactions are attributable to the

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EXPERIMENTAL SECTION

For general experimental methods, see ref 27c. Note: 1H and 13C NMR spectra were recorded in CDCl3 on an instrument at 400 (or 500) and 100 (or 125) MHz, respectively. HRMS spectra were recorded by an electrospray ionization−Fourier transform ion cyclotron resonance (ESI- FTICR) mass spectrometer. General Procedure for the Synthesis of 5-Methoxyoxazole Derivatives (General Procedure A). To a round-bottom flask charged with Cp2ZrHCl (77 mg, 0.30 mmol for tert-amides; 114 mg, 0.44 mmol for sec-amides) was added a solution of amide 1 (0.2 mmol) in THF (2.0 mL) at room temperature. The reaction mixture was stirred for 30 min, and then ZnCl2 (40 μL, 1.0 M in Et2O, 0.04 mmol), 2-aryl-substituted isocyanoacetate 3 (0.24 mmol), and triethylamine (56 μL, 0.4 mmol) were added successively. After being stirred for 2 h, the reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel to afford the desired 5methoxyoxazole derivative 4. General Procedure for the Synthesis of 2-Imidazoline Derivatives (General Procedure B). A round-bottom flask was charged with Cp2ZrHCl (83 mg, 0.32 mmol) and THF (2.0 mL). After cooling to −25 °C, a solution of sec-amide 2 (0.2 mmol) in THF (2.0 mL) was added. The reaction mixture was allowed to warm to 9696

DOI: 10.1021/acs.joc.7b01768 J. Org. Chem. 2017, 82, 9693−9703

Article

The Journal of Organic Chemistry room temperature and stirred for 30 min, and then ZnCl2 (40 μL, 1.0 M in Et2O, 0.04 mmol), 2-aryl-substituted isocyanoacetate 3 (0.24 mmol), and triethylamine (56 μL, 0.4 mmol) were added successively. After being stirred for 2 h, the reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel to afford the desired 2-imidazoline derivative 5. 5-Methoxy-4-(4-nitrophenyl)-2-(1-(pyrrolidin-1-yl)hexyl)oxazole (4a). Following general procedure A, the reaction of the 1-(pyrrolidin1-yl)hexan-1-one 1a (34 mg, 0.2 mmol) with Cp2ZrHCl (77 mg, 0.3 mmol), ZnCl2 (40 μL, 1.0 M in Et2O, 0.04 mmol), 2-isocyano-2-(4nitrophenyl)acetate 3a (53 mg, 0.24 mmol), and Et3N (56 μL, 0.4 mmol) afforded 5-methoxyoxazole 4a (67 mg, yield: 90%) as a yellow oil after flash column chromatography on silica gel (eluent: EtOAc/nhexane = 1/2). IR (film) νmax 3074, 2955, 2930, 2870, 1632, 1601, 1513, 1460, 1380, 1335, 1109, 854 cm−1; 1H NMR (400 MHz, CDCl3) δ 0.86 (t, J = 6.9 Hz, 3H), 1.15−1.39 (m, 6H), 1.73−1.85 (m, 4H), 1.85−2.02 (m, 2H), 2.49−2.60 (m, 2H), 2.67−2.77 (m, 2H), 3.58 (dd, J = 5.4, 9.4 Hz, 1H), 4.16 (s, 3H), 7.91−7.97 (m, 2H), 8.19− 8.24 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 13.9, 22.4, 23.3 (2C), 25.8, 31.6, 32.3, 51.0 (2C), 59.7, 62.1, 111.6, 123.9 (2C), 124.9 (2C), 138.3, 145.4, 154.9, 156.1; HRMS-ESI calcd for [C20H27N3O4 + Na]+ (M + Na)+: 396.1894; found: 396.1895. 5-Methoxy-4-(4-nitrophenyl)-2-(1-(pyrrolidin-1-yl)undecyl)oxazole (4b). Following general procedure A, the reaction of the 1(pyrrolidin-1-yl)undecan-1-one 1b (48 mg, 0.2 mmol) with Cp2ZrHCl (77 mg, 0.3 mmol), ZnCl2 (40 μL, 1.0 M in Et2O, 0.04 mmol), 2isocyano-2-(4-nitrophenyl)acetate 3a (53 mg, 0.24 mmol), and Et3N (56 μL, 0.4 mmol) afforded 5-methoxyoxazole 4b (76 mg, yield: 86%) as a yellow solid after flash column chromatography on silica gel (eluent: EtOAc/n-hexane = 1/5). Mp 47−48 °C. IR (film) νmax 3078, 2925, 2854, 1633, 1601, 1514, 1458, 1380, 1335, 1109, 1024, 854, 757 cm−1; 1H NMR (400 MHz, CDCl3) δ 0.86 (t, J = 6.9 Hz, 3H), 1.14− 1.40 (m, 16H), 1.72−1.85 (m, 4H), 1.86−2.02 (m, 2H), 2.50−2.62 (m, 2H), 2.66−2.77 (m, 2H), 3.59 (dd, J = 5.4, 9.3 Hz, 1H), 4.16 (s, 3H), 7.91−7.97 (m, 2H), 8.18−8.24 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 14.0, 22.6, 23.3 (2C), 26.1, 29.2, 29.3, 29.4, 29.5 (2C), 31.8, 32.3, 50.9 (2C), 59.7, 62.0, 111.6, 123.9 (2C), 124.9 (2C), 138.3, 145.5, 155.0, 156.1; HRMS-ESI calcd for [C25H37N3O4 + H]+ (M + H)+: 444.2857; found: 444.2859. 5-Methoxy-2-(2-methyl-1-(pyrrolidin-1-yl)propyl)-4-(4nitrophenyl)oxazole (4c). Following general procedure A, the reaction of the 2-methyl-1-(pyrrolidin-1-yl)propan-1-one 1c (28 mg, 0.2 mmol) with Cp2ZrHCl (77 mg, 0.3 mmol), ZnCl2 (40 μL, 1.0 M in Et2O, 0.04 mmol), 2-isocyano-2-(4-nitrophenyl)acetate 3a (53 mg, 0.24 mmol), and Et3N (56 μL, 0.4 mmol) afforded 5-methoxyoxazole 4c (65 mg, yield: 94%) as a yellow oil after flash column chromatography on silica gel (eluent: EtOAc/n-hexane = 1/5). IR (film) νmax 3078, 2960, 2927, 2872, 2802, 1633, 1601, 1513, 1460, 1383, 1335, 1109, 1024, 967, 854, 758 cm−1; 1H NMR (400 MHz, CDCl3) δ 0.96 (d, J = 6.8 Hz, 3H), 1.02 (d, J = 6.7 Hz, 3H), 1.69−1.80 (m, 4H), 2.18−2.32 (m, 1H), 2.49−2.60 (m, 2H), 2.62−2.73 (m, 2H), 3.39 (d, J = 8.2 Hz, 1H), 4.15 (s, 3H), 7.91−7.97 (m, 2H), 8.18−8.24 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 18.8, 20.1, 23.3 (2C), 30.1, 50.3 (2C), 59.6, 67.4, 111.6, 123.9 (2C), 125.0 (2C), 138.4, 145.5, 154.5, 156.0; HRMS-ESI calcd for [C18H23N3O4 + Na]+ (M + Na)+: 368.1581; found: 368.1582. 2-(Cyclohexyl(pyrrolidin-1-yl)methyl)-5-methoxy-4-(4nitrophenyl)oxazole (4d). Following general procedure A, the reaction of the cyclohexyl(pyrrolidin-1-yl)methanone 1d (36 mg, 0.2 mmol) with Cp2ZrHCl (77 mg, 0.3 mmol), ZnCl2 (40 μL, 1.0 M in Et2O, 0.04 mmol), 2-isocyano-2-(4-nitrophenyl)acetate 3a (53 mg, 0.24 mmol), and Et3N (56 μL, 0.4 mmol) afforded 5-methoxyoxazole 4d (70 mg, yield: 91%) as a yellow solid after flash column chromatography on silica gel (eluent: EtOAc/n-hexane = 1/10). Mp 91−93 °C. IR (film) νmax 3078, 2925, 2851, 1632, 1601, 1513, 1449, 1381, 1334, 1109, 1024, 854, 757 cm−1; 1H NMR (400 MHz, CDCl3) δ 0.81−1.37 (m, 5H), 1.58−1.84 (m, 8H), 1.86−2.05 (m, 2H), 2.48− 2.62 (m, 2H), 2.62−2.76 (m, 2H), 3.49 (d, J = 8.5 Hz, 1H), 4.15 (s, 3H), 7.90−7.97 (m, 2H), 8.17−8.25 (m, 2H); 13C NMR (100 MHz,

CDCl3) δ 23.3 (2C), 26.1, 26.2, 26.6, 30.0, 30.8, 39.7, 50.0 (2C), 59.6, 66.3, 111.6, 123.9 (2C), 125.0 (2C), 138.4, 145.4, 154.5, 156.0; HRMS-ESI calcd for [C21H27N3O4 + Na]+ (M + Na)+: 408.1894; found: 408.1897. 2-(2,2-Dimethyl-1-(pyrrolidin-1-yl)propyl)-5-methoxy-4-(4nitrophenyl)oxazole (4e). Following general procedure A, the reaction of the 2,2-dimethyl-1-(pyrrolidin-1-yl)propan-1-one 1e (31 mg, 0.2 mmol) with Cp2ZrHCl (77 mg, 0.3 mmol), ZnCl2 (40 μL, 1.0 M in Et2O, 0.04 mmol), 2-isocyano-2-(4-nitrophenyl)acetate 3a (53 mg, 0.24 mmol), and Et3N (56 μL, 0.4 mmol) afforded 5methoxyoxazole 4e (25 mg, yield: 35%) as a yellow oil after flash column chromatography on silica gel (eluent: EtOAc/n-hexane = 1/ 20). IR (film) νmax 3078, 2955, 2870, 2805, 1633, 1601, 1513, 1460, 1381, 1334, 1109, 1024, 966, 854, 758 cm−1; 1H NMR (400 MHz, CDCl3) δ 1.09 (s, 9H), 1.60−1.79 (m, 4H), 2.63−2.81 (m, 4H), 3.60 (s, 1H), 4.15 (s, 3H), 7.90−7.97 (m, 2H), 8.18−8.25 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 23.8 (2C), 27.9 (3C), 35.9, 52.3 (2C), 59.5, 69.0, 111.1, 123.9 (2C), 124.9 (2C), 138.5, 145.4, 154.5, 155.8; HRMS-ESI calcd for [C19H25N3O4 + Na]+ (M+Na)+: 382.1737; found: 382.1737. 5-Methoxy-4-(4-nitrophenyl)-2-(phenyl(pyrrolidin-1-yl)methyl)oxazole (4f). Following general procedure A, the reaction of the phenyl(pyrrolidin-1-yl)methanone 1f (35 mg, 0.2 mmol) with Cp2ZrHCl (77 mg, 0.3 mmol), ZnCl2 (40 μL, 1.0 M in Et2O, 0.04 mmol), 2-isocyano-2-(4-nitrophenyl)acetate 3a (53 mg, 0.24 mmol), and Et3N (56 μL, 0.4 mmol) afforded 5-methoxyoxazole 4f (63 mg, yield: 83%) as a yellow solid after flash column chromatography on silica gel (eluent: EtOAc/n-hexane = 1/5). Decomposed at 137 °C. IR (film) νmax 3062, 3026, 2959, 2874, 2799, 1632, 1601, 1512, 1454, 1382, 1333, 1109, 1024, 855, 757, 670 cm−1; 1H NMR (400 MHz, CDCl3) δ 1.77−1.88 (m, 4H), 2.46−2.63 (m, 4H), 4.12 (s, 3H), 4.45 (s, 1H), 7.27−7.39 (m, 3H), 7.55−7.61 (m, 2H), 7.78−7.95 (m, 2H), 8.17−8.22 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 23.4 (2C), 52.9 (2C), 59.7, 68.8, 111.8, 123.9 (2C), 124.9 (2C), 128.1, 128.2 (2C), 128.6 (2C), 138.2, 138.3, 145.4, 154.3, 156.2; HRMS-ESI calcd for [C21H21N3O4 + Na]+ (M + Na)+: 402.1424; found: 402.1425. 2-((4-Fluorophenyl)(pyrrolidin-1-yl)methyl)-5-methoxy-4-(4nitrophenyl)oxazole (4g). Following general procedure A, the reaction of the (4-fluorophenyl)(pyrrolidin-1-yl)methanone 1g (39 mg, 0.2 mmol) with Cp2ZrHCl (77 mg, 0.3 mmol), ZnCl2 (40 μL, 1.0 M in Et2O, 0.04 mmol), 2-isocyano-2-(4-nitrophenyl)acetate 3a (53 mg, 0.24 mmol), and Et3N (56 μL, 0.4 mmol) afforded 5methoxyoxazole 4g (61 mg, yield: 77%) as a yellow oil after flash column chromatography on silica gel (eluent: EtOAc/n-hexane = 1/ 4). IR (film) νmax 3071, 2959, 2875, 2801, 1633, 1602, 1509, 1460, 1382, 1334, 1223, 1109, 1024, 853, 758 cm−1; 1H NMR (400 MHz, CDCl3) δ 1.76−1.90 (m, 4H), 2.44−2.61 (m, 4H), 4.13 (s, 3H), 4.44 (s, 1H), 7.00−7.10 (m, 2H), 7.51−7.61 (m, 2H), 7.87−7.96 (m, 2H), 8.16−8.24 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 23.3 (2C), 52.9 (2C), 59.7, 67.9, 111.8, 115.4 (d, JF−C = 21.6 Hz, 2C) 123.9 (2C), 124.9 (2C), 129.8 (d, JF−C = 8.1 Hz, 2C), 134.2 (d, JF−C = 3.1 Hz), 138.1, 145.4, 154.0, 156.2, 162.5 (d, JF−C = 246.6 Hz); HRMS-ESI calcd for [C21H20FN3O4 + H]+ (M + H)+: 398.1511; found: 398.1513. 5-Methoxy-4-(4-nitrophenyl)-2-(pyrrolidin-1-yl(4(trifluoromethyl)phenyl)methyl)oxazole (4h). Following general procedure A, the reaction of the pyrrolidin-1-yl(4-(trifluoromethyl)phenyl)methanone 1h (49 mg, 0.2 mmol) with Cp2ZrHCl (77 mg, 0.3 mmol), ZnCl2 (40 μL, 1.0 M in Et2O, 0.04 mmol), 2-isocyano-2-(4nitrophenyl)acetate 3a (53 mg, 0.24 mmol), and Et3N (56 μL, 0.4 mmol) afforded 5-methoxyoxazole 4h (78 mg, yield: 87%) as a yellow oil after flash column chromatography on silica gel (eluent: EtOAc/nhexane = 1/6). IR (film) νmax 3071, 2960, 2873, 2803, 1633, 1602, 1513, 1459, 1383, 1326, 1164, 1126, 1067, 1022, 854 cm−1; 1H NMR (400 MHz, CDCl3) δ 1.79−1.90 (m, 4H), 2.46−2.64 (m, 4H), 4.14 (s, 3H), 4.54 (s, 1H), 7.60−7.67 (m, 2H), 7.69−7.77 (m, 2H), 7.87−7.95 (m, 2H), 8.16−8.24 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 23.4 (2C), 52.8 (2C), 59.7, 68.1, 112.0, 124.0 (q, JF−C = 272.0 Hz), 123.9 (2C), 124.9 (2C), 125.6 (q, JF−C = 3.7 Hz, 2C), 128.6 (2C), 130.3 (q, JF−C = 32.6 Hz), 137.9, 142.3, 145.5, 153.4, 156.3; HRMS-ESI calcd for [C22H20F3N3O4 + H]+ (M + H)+: 448.1479; found: 448.1450. 9697

DOI: 10.1021/acs.joc.7b01768 J. Org. Chem. 2017, 82, 9693−9703

Article

The Journal of Organic Chemistry

gel (eluent: EtOAc/n-hexane = 2/1). IR (film) νmax 3033, 2959, 2873, 2802, 1632, 1602, 1512, 1458, 1382, 1333, 1109, 1024, 855, 712 cm−1; 1 H NMR (400 MHz, CDCl3) δ 1.78−1.90 (m, 4H), 2.47−2.64 (m, 4H), 4.14 (s, 3H), 4.53 (s, 1H), 7.29−7.35 (m, 1H), 7.88−7.99 (m, 3H), 8.17−8.24 (m, 2H), 8.54−8.61 (m, 1H), 8.77−8.83 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 23.4 (2C), 52.7 (2C), 59.7, 66.0, 112.0, 123.6, 123.9 (2C), 124.9 (2C), 134.0, 135.8, 137.9, 145.5, 149.6, 149.7, 153.2, 156.3; HRMS-ESI calcd for [C20H20N4O4 + H]+ (M + H)+: 381.1557; found: 381.1559. 2-(Furan-2-yl(pyrrolidin-1-yl)methyl)-5-methoxy-4-(4nitrophenyl)oxazole (4n). Following general procedure A, the reaction of the furan-2-yl(pyrrolidin-1-yl)methanone 1n (33 mg, 0.2 mmol) with Cp2ZrHCl (77 mg, 0.3 mmol), ZnCl2 (40 μL, 1.0 M in Et2O, 0.04 mmol), 2-isocyano-2-(4-nitrophenyl)acetate 3a (53 mg, 0.24 mmol), and Et3N (56 μL, 0.4 mmol) afforded 5-methoxyoxazole 4n (63 mg, yield: 88%) as a yellow solid after flash column chromatography on silica gel (eluent: EtOAc/n-hexane = 1/4). Decomposed at 116 °C. IR (film) νmax 3110, 2959, 2876, 2807, 1633, 1602, 1512, 1459, 1382, 1335, 1109, 1024, 854, 757, 739 cm−1; 1 H NMR (400 MHz, CDCl3) δ 1.79−1.88 (m, 4H), 2.55−2.70 (m, 4H), 4.18 (s, 3H), 4.77 (s, 1H), 6.35−6.39 (m, 1H), 6.42−6.45 (m, 1H), 7.42−7.44 (m, 1H), 7.91−7.96 (m, 2H), 8.18−8.24 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 23.3 (2C), 52.0 (2C), 59.8, 60.5, 108.9, 110.3, 112.0, 123.9 (2C), 124.9 (2C), 138.0, 142.6, 145.5, 150.5, 152.0, 156.3; HRMS-ESI calcd for [C19H19N3O5 + Na]+ (M + Na)+: 392.1217; found: 392.1216. 5-Methoxy-4-(4-nitrophenyl)-2-(pyrrolidin-1-yl(thiophen-2-yl)methyl)oxazole (4o). Following general procedure A, the reaction of the pyrrolidin-1-yl(thiophen-2-yl)methanone 1o (36 mg, 0.2 mmol) with Cp2ZrHCl (77 mg, 0.3 mmol), ZnCl2 (40 μL, 1.0 M in Et2O, 0.04 mmol), 2-isocyano-2-(4-nitrophenyl)acetate 3a (53 mg, 0.24 mmol), and Et3N (56 μL, 0.4 mmol) afforded 5-methoxyoxazole 4o (72 mg, yield: 93%) as a yellow solid after flash column chromatography on silica gel (eluent: EtOAc/n-hexane = 1/5). Decomposed at 138 °C. IR (film) νmax 3110, 3071, 2959, 2802, 1631, 1601, 1511, 1458, 1382, 1333, 1109, 1023, 854, 704 cm−1; 1H NMR (400 MHz, CDCl3) δ 1.79−1.87 (m, 4H), 2.52−2.62 (m, 2H), 2.62−2.71 (m, 2H), 4.17 (s, 3H), 4.87 (s, 1H), 6.93−6.99 (m, 1H), 7.10−7.15 (m, 1H), 7.29−7.34 (m, 1H), 7.89−7.95 (m, 2H), 8.17−8.23 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 23.4 (2C), 52.5 (2C), 59.8, 63.2, 111.8, 123.9 (2C), 124.9 (2C), 126.1, 126.3 (2C), 138.0, 141.3, 145.5, 153.3, 156.2; HRMS-ESI calcd for [C19H19N3O4S + Na]+ (M + Na)+: 408.0988; found: 408.0988. 5-Methoxy-4-(4-nitrophenyl)-2-(1-(piperidin-1-yl)hexyl)oxazole (4p). Following general procedure A, the reaction of the 1-(piperidin1-yl)hexan-1-one 1p (37 mg, 0.2 mmol) with Cp2ZrHCl (77 mg, 0.3 mmol), ZnCl2 (40 μL, 1.0 M in Et2O, 0.04 mmol), 2-isocyano-2-(4nitrophenyl)acetate 3a (53 mg, 0.24 mmol), and Et3N (56 μL, 0.4 mmol) afforded 5-methoxyoxazole 4p (64 mg, yield: 83%) as a yellow oil after flash column chromatography on silica gel (eluent: EtOAc/nhexane = 1/10). IR (film) νmax 3078, 2932, 2856, 2805, 1632, 1601, 1513, 1456, 1381, 1335, 1108, 1024, 854, 757 cm−1; 1H NMR (400 MHz, CDCl3) δ 0.88 (t, J = 6.8 Hz, 3H), 1.20−1.45 (m, 8H), 1.49− 1.68 (m, 4H), 1.79−2.02 (m, 2H), 2.37−2.50 (m, 2H), 2.52−2.65 (m, 2H), 3.60 (dd, J = 6.2, 9.0 Hz, 1H), 4.16 (s, 3H), 7.90−7.97 (m, 2H), 8.18−8.25 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 13.9, 22.4, 24.5, 26.1, 26.3 (2C), 30.1, 31.6, 50.9 (2C), 59.5, 63.6, 111.5, 123.9 (2C), 124.9 (2C), 138.5, 145.4, 154.5, 156.0; HRMS-ESI calcd for [C21H29N3O4 + Na]+ (M + Na)+: 410.2050; found: 410.2052. N,N-Diethyl-1-(5-methoxy-4-(4-nitrophenyl)oxazol-2-yl)hexan-1amine (4q). Following general procedure A, the reaction of the N,Ndiethylhexanamide 1q (34 mg, 0.2 mmol) with Cp2ZrHCl (77 mg, 0.3 mmol), ZnCl2 (40 μL, 1.0 M in Et2O, 0.04 mmol), 2-isocyano-2-(4nitrophenyl)acetate 3a (53 mg, 0.24 mmol), and Et3N (56 μL, 0.4 mmol) afforded 5-methoxyoxazole 4q (56 mg, yield: 75%) as a yellow solid after flash column chromatography on silica gel (eluent: EtOAc/ n-hexane = 1/10). Mp 30−31 °C. IR (film) νmax 3078, 2959, 2931, 2859, 1633, 1601, 1514, 1455, 1381, 1334, 1109, 1025, 854, 757 cm−1; 1 H NMR (400 MHz, CDCl3) δ 0.89 (t, J = 7.0 Hz, 3H), 1.07 (t, J = 7.1 Hz, 6H), 1.24−1.49 (m, 6H), 1.75−1.98 (m, 2H), 2.35−2.48 (m,

5-Methoxy-4-(4-nitrophenyl)-2-((4-nitrophenyl)(pyrrolidin-1-yl)methyl)oxazole (4i). Following general procedure A, the reaction of the (4-nitrophenyl)(pyrrolidin-1-yl)methanone 1i (44 mg, 0.2 mmol) with Cp2ZrHCl (77 mg, 0.3 mmol), ZnCl2 (40 μL, 1.0 M in Et2O, 0.04 mmol), 2-isocyano-2-(4-nitrophenyl)acetate 3a (53 mg, 0.24 mmol), and Et3N (56 μL, 0.4 mmol) afforded 5-methoxyoxazole 4i (57 mg, yield: 67%) as a yellow oil after flash column chromatography on silica gel (eluent: EtOAc/n-hexane = 1/3). IR (film) νmax 3074, 2958, 2873, 2804, 1631, 1560, 1460, 1383, 1346, 1109, 854 cm−1; 1H NMR (400 MHz, CDCl3) δ 1.81−1.91 (m, 4H), 2.46−2.65 (m, 4H), 4.14 (s, 3H), 4.61 (s, 1H), 7.76−7.82 (m, 2H), 7.88−7.93 (m, 2H), 8.17−8.26 (m, 4H); 13C NMR (100 MHz, CDCl3) δ 23.4 (2C), 52.7 (2C), 59.8, 67.7, 112.2, 123.9 (4C), 124.9 (2C), 129.1 (2C), 137.8, 145.5, 145.6, 147.7, 152.7, 156.4; HRMS-ESI calcd for [C21H20N4O6 + Na]+ (M + Na)+: 447.1275; found: 447.1277. 4-((5-Methoxy-4-(4-nitrophenyl)oxazol-2-yl)(pyrrolidin-1-yl)methyl)benzonitrile (4j). Following general procedure A, the reaction of the 4-(pyrrolidine-1-carbonyl)benzonitrile 1j (40 mg, 0.2 mmol) with Cp2ZrHCl (77 mg, 0.3 mmol), ZnCl2 (40 μL, 1.0 M in Et2O, 0.04 mmol), 2-isocyano-2-(4-nitrophenyl)acetate 3a (53 mg, 0.24 mmol), and Et3N (56 μL, 0.4 mmol) afforded 5-methoxyoxazole 4j (62 mg, yield: 77%) as a yellow oil after flash column chromatography on silica gel (eluent: EtOAc/n-hexane = 1/3). IR (film) νmax 3068, 2960, 2930, 2876, 2803, 2228, 1631, 1601, 1512, 1458, 1383, 1335, 1109, 1023, 853 cm−1; 1H NMR (400 MHz, CDCl3) δ 1.80−1.89 (m, 4H), 2.45− 2.62 (m, 4H), 4.13 (s, 3H), 4.55 (s, 1H), 7.64−7.70 (m, 2H), 7.70− 7.75 (m, 2H), 7.88−7.93 (m, 2H), 8.17−8.23 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 23.4 (2C), 52.7 (2C), 59.7, 68.0, 112.1, 112.2, 118.5, 123.9 (2C), 124.9 (2C), 129.0 (2C), 132.4 (2C), 137.8, 143.6, 145.6, 152.9, 156.3; HRMS-ESI calcd for [C22H20N4O4 + Na]+ (M + Na)+: 427.1377; found: 427.1379. 5-Methoxy-4-(4-nitrophenyl)-2-(pyrrolidin-1-yl(p-tolyl)methyl)oxazole (4k). Following general procedure A, the reaction of the pyrrolidin-1-yl(p-tolyl)methanone 1k (38 mg, 0.2 mmol) with Cp2ZrHCl (77 mg, 0.3 mmol), ZnCl2 (40 μL, 1.0 M in Et2O, 0.04 mmol), 2-isocyano-2-(4-nitrophenyl)acetate 3a (53 mg, 0.24 mmol), and Et3N (56 μL, 0.4 mmol) afforded 5-methoxyoxazole 4k (65 mg, yield: 83%) as a yellow oil after flash column chromatography on silica gel (eluent: EtOAc/n-hexane = 1/3). IR (film) νmax 3068, 2957, 2874, 2798, 1632, 1601, 1512, 1458, 1381, 1333, 1109, 1024, 854 cm−1; 1H NMR (400 MHz, CDCl3) δ 1.75−1.89 (m, 4H), 2.34 (s, 3H), 2.46− 2.61 (m, 4H), 4.12 (s, 3H), 4.41 (s, 1H), 7.13−7.20 (m, 2H), 7.42− 7.51 (m, 2H), 7.87−7.95 (m, 2H), 8.15−8.24 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 21.1, 23.3 (2C), 52.9 (2C), 59.6, 68.6, 111.8, 123.8 (2C), 124.9 (2C), 128.1 (2C), 129.2 (2C), 135.3, 137.9, 138.2, 145.3, 154.5, 156.2; HRMS-ESI calcd for [C22H23N3O4 + Na]+ (M + Na)+: 416.1581; found: 416.1581. 5-Methoxy-2-((4-methoxyphenyl)(pyrrolidin-1-yl)methyl)-4-(4nitrophenyl)oxazole (4l). Following general procedure A, the reaction of the (4-methoxyphenyl)(pyrrolidin-1-yl)methanone 1l (41 mg, 0.2 mmol) with Cp2ZrHCl (77 mg, 0.3 mmol), ZnCl2 (40 μL, 1.0 M in Et2O, 0.04 mmol), 2-isocyano-2-(4-nitrophenyl)acetate 3a (53 mg, 0.24 mmol), and Et3N (56 μL, 0.4 mmol) afforded 5-methoxyoxazole 4l (68 mg, yield: 83%) as a yellow oil after flash column chromatography on silica gel (eluent: EtOAc/n-hexane = 1/4). IR (film) νmax 3068, 2957, 2799, 1632, 1602, 1511, 1459, 1382, 1334, 1248, 1175, 1109, 1024, 854 cm−1; 1H NMR (400 MHz, CDCl3) δ 1.77−1.88 (m, 4H), 2.45−2.61 (m, 4H), 3.80 (s, 3H), 4.12 (s, 3H), 4.39 (s, 1H), 6.86−6.92 (m, 2H), 7.46−7.54 (m, 2H), 7.88−7.96 (m, 2H), 8.15−8.24 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 23.4 (2C), 52.9 (2C), 55.2, 59.7, 68.1, 111.8, 113.9 (2C), 123.9 (2C), 124.9 (2C), 129.3 (2C), 130.5, 138.2, 145.4, 154.6, 156.2, 159.4; HRMS-ESI calcd for [C22H23N3O5 + Na]+ (M + Na)+: 432.1530; found: 432.1530. 5-Methoxy-4-(4-nitrophenyl)-2-(pyridin-3-yl(pyrrolidin-1-yl)methyl)oxazole (4m). Following general procedure A, the reaction of the pyridin-3-yl(pyrrolidin-1-yl)methanone 1m (35 mg, 0.2 mmol) with Cp2ZrHCl (77 mg, 0.3 mmol), ZnCl2 (40 μL, 1.0 M in Et2O, 0.04 mmol), 2-isocyano-2-(4-nitrophenyl)acetate 3a (53 mg, 0.24 mmol), and Et3N (56 μL, 0.4 mmol) afforded 5-methoxyoxazole 4m (67 mg, yield: 88%) as a yellow oil after flash column chromatography on silica 9698

DOI: 10.1021/acs.joc.7b01768 J. Org. Chem. 2017, 82, 9693−9703

Article

The Journal of Organic Chemistry 2H), 2.69−2.82 (m, 2H), 3.82 (dd, J = 7.1, 7.9 Hz, 1H), 4.14 (s, 3H), 7.90−7.95 (m, 2H), 8.18−8.23 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 13.8 (2C), 14.0, 22.5, 26.2, 30.5, 31.6, 44.4 (2C), 58.3, 59.5, 111.5, 123.9 (2C), 124.9 (2C), 138.5, 145.4, 155.4, 156.0; HRMS-ESI calcd for [C20H29N3O4 + Na]+ (M + Na)+: 398.2050; found: 398.2052. 1-(5-Methoxy-4-(4-nitrophenyl)oxazol-2-yl)-N,N-dimethylhexan1-amine (4r). Following general procedure A, the reaction of the N,Ndimethylhexanamide 1r (29 mg, 0.2 mmol) with Cp2ZrHCl (77 mg, 0.3 mmol), ZnCl2 (40 μL, 1.0 M in Et2O, 0.04 mmol), 2-isocyano-2(4-nitrophenyl)acetate 3a (53 mg, 0.24 mmol), and Et3N (56 μL, 0.4 mmol) afforded 5-methoxyoxazole 4r (52 mg, yield: 75%) as a yellow oil after flash column chromatography on silica gel (eluent: EtOAc/nhexane = 1/2). IR (film) νmax 3078, 2953, 2933, 2860, 2784, 1632, 1601, 1513, 1457, 1380, 1337, 1175, 1108, 1024, 854 cm−1; 1H NMR (400 MHz, CDCl3) δ 0.88 (t, J = 7.0 Hz, 3H), 1.21−1.44 (m, 6H), 1.78−1.99 (m, 2H), 2.33 (s, 6H), 3.59 (dd, J = 6.3, 8.8 Hz, 1H), 4.16 (s, 3H), 7.91−7.96 (m, 2H), 8.18−8.24 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 13.9, 22.4, 26.0, 30.3, 31.6, 41.8 (2C), 59.5, 63.1, 111.6, 123.9 (2C), 124.9 (2C), 138.4, 145.4, 154.1, 156.1; HRMS-ESI calcd for [C18H25N3O4 + Na]+ (M + Na)+: 370.1737; found: 370.1738. N-Benzyl-1-(5-methoxy-4-(4-nitrophenyl)oxazol-2-yl)-N-methylhexan-1-amine (4s). Following general procedure A, the reaction of the N-benzyl-N-methylhexanamide 1s (44 mg, 0.2 mmol) with Cp2ZrHCl (77 mg, 0.3 mmol), ZnCl2 (40 μL, 1.0 M in Et2O, 0.04 mmol), 2-isocyano-2-(4-nitrophenyl)acetate 3a (53 mg, 0.24 mmol), and Et3N (56 μL, 0.4 mmol) afforded 5-methoxyoxazole 4s (68 mg, yield: 80%) as a yellow oil after flash column chromatography on silica gel (eluent: EtOAc/n-hexane = 1/10). IR (film) νmax 3058, 3028, 2952, 2858, 2797, 1632, 1601, 1512, 1454, 1381, 1335, 1109, 1024, 854, 757, 735, 699 cm−1; 1H NMR (400 MHz, CDCl3) δ 0.89 (t, J = 6.9 Hz, 3H), 1.26−1.39 (m, 5H), 1.42−1.54 (m, 1H), 1.90−2.00 (m, 2H), 2.26 (s, 3H), 3.53 (d, J = 13.5 Hz, 1H), 3.75 (d, J = 13.5 Hz, 1H), 3.77 (dd, J = 7.6, 7.6 Hz, 1H), 4.17 (s, 3H), 7.22−7.28 (m, 1H), 7.29− 7.38 (m, 4H), 7.92−7.98 (m, 2H), 8.20−8.25 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 14.0, 22.5, 26.0, 30.0, 31.5, 37.9, 58.7, 59.5, 60.8, 111.6, 123.9 (2C), 124.9 (2C), 127.0, 128.2 (2C), 128.8 (2C), 138.4, 139.3, 145.4, 154.5, 156.0; HRMS-ESI calcd for [C24H29N3O4 + Na]+ (M + Na)+: 446.2050; found: 446.2052. N,N-Dibenzyl-1-(5-methoxy-4-(4-nitrophenyl)oxazol-2-yl)hexan1-amine (4t). Following general procedure A, the reaction of the N,Ndibenzylhexanamide 1t (59 mg, 0.2 mmol) with Cp2ZrHCl (77 mg, 0.3 mmol), ZnCl2 (40 μL, 1.0 M in Et2O, 0.04 mmol), 2-isocyano-2(4-nitrophenyl)acetate 3a (53 mg, 0.24 mmol), and Et3N (56 μL, 0.4 mmol) afforded 5-methoxyoxazole 4t (38 mg, yield: 38%) as a yellow solid after flash column chromatography on silica gel (eluent: EtOAc/ n-hexane = 1/50). Mp 67−69 °C. IR (film) νmax 3062, 3028, 2953, 2930, 2857, 1631, 1601, 1512, 1454, 1380, 1335, 1109, 1025, 854, 746, 698 cm−1; 1H NMR (400 MHz, CDCl3) δ 0.84 (t, J = 7.2 Hz, 3H), 1.11−1.21 (m, 2H), 1.21−1.36 (m, 3H), 1.40−1.53 (m, 1H), 1.84− 2.06 (m, 2H), 3.39 (d, J = 13.7 Hz, 2H), 3.79 (dd, J = 7.5, 7.5 Hz, 1H), 3.94 (d, J = 13.7 Hz, 2H), 4.19 (s, 3H), 7.22−7.28 (m, 2H), 7.29−7.36 (m, 4H), 7.38−7.44 (m, 4H), 7.94−8.00 (m, 2H), 8.21−8.27 (m, 2H); 13 C NMR (100 MHz, CDCl3) δ 14.0, 22.5, 25.9, 29.8, 31.4, 54.6 (2C), 56.0, 59.5, 111.6, 124.0 (2C), 124.9 (2C), 127.0 (2C), 128.3 (4C), 128.9 (4C), 138.5, 139.5 (2C), 145.5, 154.6, 156.0; HRMS-ESI calcd for [C30H33N3O4 + Na]+ (M + Na)+: 522.2363; found: 522.2366. N-(1-(5-Methoxy-4-(4-nitrophenyl)oxazol-2-yl)hexyl)-N-methylaniline (4u). Following general procedure A, the reaction of the Nmethyl-N-phenylhexanamide 1u (41 mg, 0.2 mmol) with Cp2ZrHCl (77 mg, 0.3 mmol), ZnCl2 (40 μL, 1.0 M in Et2O, 0.04 mmol), 2isocyano-2-(4-nitrophenyl)acetate 3a (53 mg, 0.24 mmol), and Et3N (56 μL, 0.4 mmol) afforded 5-methoxyoxazole 4u (21 mg, yield: 26%) as a yellow solid after flash column chromatography on silica gel (eluent: EtOAc/n-hexane = 1/40). Mp 50−52 °C. IR (film) νmax 3062, 3023, 2953, 2928, 2858, 1632, 1599, 1505, 1456, 1381, 1334, 1109, 1024, 854, 750, 692 cm−1; 1H NMR (400 MHz, CDCl3) δ 0.88 (t, J = 7.1 Hz, 3H), 1.26−1.49 (m, 6H), 1.97−2.20 (m, 2H), 2.84 (s, 3H), 4.04 (s, 3H), 4.88 (dd, J = 6.7, 8.4 Hz, 1H), 6.76−6.81 (m, 1H), 6.89−

6.95 (m, 2H), 7.23−7.31 (m, 2H), 7.88−7.94 (m, 2H), 8.17−8.24 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 14.0, 22.5, 25.9, 30.1, 31.5, 32.2, 57.2, 59.5, 111.6, 113.9 (2C), 117.8, 123.9 (2C), 124.9 (2C), 129.2 (2C), 138.3, 145.4, 150.1, 154.3, 156.0; HRMS-ESI calcd for [C23H27N3O4 + Na]+ (M + Na)+: 432.1894; found: 432.1895. Methyl 4-(5-Methoxy-2-(1-(pyrrolidin-1-yl)hexyl)oxazol-4-yl)benzoate (4v). Following general procedure A, the reaction of the 1-(pyrrolidin-1-yl)hexan-1-one 1a (34 mg, 0.2 mmol) with Cp2ZrHCl (77 mg, 0.3 mmol), ZnCl2 (40 μL, 1.0 M in Et2O, 0.04 mmol), methyl 4-(1-isocyano-2-methoxy-2-oxoethyl)benzoate 3b (47 mg, 0.24 mmol), and Et3N (56 μL, 0.4 mmol) afforded 5-methoxyoxazole 4v (50 mg, yield: 65%) as a yellow oil after flash column chromatography on silica gel (eluent: EtOAc/n-hexane = 1/4). IR (film) νmax 2952, 2860, 2802, 1720, 1637, 1612, 1435, 1375, 1276, 1178, 1105, 1027, 1045, 968, 861, 776, 709 cm−1; 1H NMR (400 MHz, CDCl3) δ 0.86 (t, J = 6.9 Hz, 3H), 1.15−1.38 (m, 6H), 1.71−1.84 (m, 4H), 1.84−2.01 (m, 2H), 2.48−2.60 (m, 2H), 2.66−2.77 (m, 2H), 3.58 (dd, J = 5.3, 9.5 Hz, 1H), 3.91 (s, 3H), 4.11 (s, 3H), 7.85−7.90 (m, 2H), 8.01−8.06 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 13.9, 22.4, 23.3 (2C), 25.8, 31.6, 32.4, 51.0 (2C), 51.9, 59.8, 62.1, 112.9, 124.6 (2C), 127.4, 129.8 (2C), 136.2, 154.8, 155.4, 167.1; HRMS-ESI calcd for [C22H30N2O4 + Na]+ (M+Na) +: 409.2098; found: 409.2100. N-Benzyl-1-(5-methoxy-4-(4-nitrophenyl)oxazol-2-yl)-2-methylpropan-1-amine (4w). Following general procedure A, the reaction of N-benzylisobutyramide 1w (36 mg, 0.2 mmol) with Cp2ZrHCl (114 mg, 0.44 mmol), ZnCl2 (40 μL, 1.0 M in Et2O, 0.04 mmol), 2isocyano-2-(4-nitrophenyl)acetate 3a (53 mg, 0.24 mmol), and Et3N (56 μL, 0.4 mmol) afforded 5-methoxyoxazole 4w3,11a (75 mg, yield: 98%) as a yellow solid after flash column chromatography on silica gel (eluent: EtOAc/n-hexane = 1/4). Mp 87−88 °C. IR (film) νmax 3026, 2957, 2917, 2849, 1632, 1601, 1512, 1453, 1385, 1335, 1195, 1132, 1077, 1024, 854 cm−1; 1H NMR (400 MHz, CDCl3) δ 0.94 (d, J = 6.8 Hz, 3H), 1.05 (d, J = 6.8 Hz, 3H), 1.83 (s, br, 1H), 2.03−2.14 (m, 1H), 3.51 (d, J = 6.9 Hz, 1H), 3.70 (d, J = 13.3 Hz, 1H), 3.85 (d, J = 13.3 Hz, 1H), 4.12 (s, 3H), 7.20−7.27 (m, 1H), 7.27−7.36 (m, 4H), 7.90−7.96 (m, 2H), 8.19−8.25 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 19.1, 19.2, 32.7, 52.0, 59.5, 62.2, 111.7, 123.9 (2C), 124.9 (2C), 127.0, 128.2 (2C), 128.3 (2C), 138.3, 139.9, 145.4, 156.0, 156.1; HRMS-ESI calcd for [C21H23N3O4 + Na]+ (M + Na)+: 404.1581; found: 404.1590. N-Benzyl-1-cyclohexyl-1-(5-methoxy-4-(4-nitrophenyl)oxazol-2yl)methanamine (4x). Following general procedure A, the reaction of the N-benzylcyclohexanecarboxamide 1x (44 mg, 0.2 mmol) with Cp2ZrHCl (114 mg, 0.44 mmol), ZnCl2 (40 μL, 1.0 M in Et2O, 0.04 mmol), 2-isocyano-2-(4-nitrophenyl)acetate 3a (53 mg, 0.24 mmol), and Et3N (56 μL, 0.4 mmol) afforded 5-methoxyoxazole 4x (67 mg, yield: 80%) as a yellow oil after flash column chromatography on silica gel (eluent: EtOAc/n-hexane = 1/8). IR (film) νmax 3058, 3026, 2926, 2852, 1632, 1601, 1511, 1383, 1334, 1216, 1177, 1135, 1109, 1023, 964, 854, 701 cm−1; 1H NMR (500 MHz, CDCl3) δ 0.99−1.30 (m, 5H), 1.45−1.52 (m, 1H), 1.62−1.68 (m, 1H), 1.68−1.79 (m, 3H), 1.81 (s, br, 1H), 1.96−2.04 (m, 1H), 3.53 (d, J = 7.2 Hz, 1H), 3.68 (d, J = 13.3 Hz, 1H), 3.83 (d, J = 13.3 Hz, 1H), 4.12 (s, 3H), 7.20−7.25 (m, 1H), 7.27−7.34 (m, 4H), 7.91−7.96 (m, 2H), 8.20−8.25 (m, 2H); 13 C NMR (125 MHz, CDCl3) δ 26.0 (2C), 26.3, 29.6, 29.8, 42.3, 52.0, 59.6, 61.6, 111.7, 123.9 (2C), 124.9 (2C), 127.0, 128.1 (2C), 128.3 (2C), 138.4, 140.0, 145.4, 156.0, 156.1; HRMS-ESI calcd for [C24H27N3O4 + Na]+ (M + Na)+: 444.1894; found: 444.1895. N-(Cyclohexyl(5-methoxy-4-(4-nitrophenyl)oxazol-2-yl)methyl)propan-2-amine (4y). Following general procedure A, the reaction of the N-isopropylcyclohexanecarboxamide 1y (34 mg, 0.2 mmol) with Cp2ZrHCl (114 mg, 0.44 mmol), ZnCl2 (40 μL, 1.0 M in Et2O, 0.04 mmol), 2-isocyano-2-(4-nitrophenyl)acetate 3a (53 mg, 0.24 mmol), and Et3N (56 μL, 0.4 mmol) afforded 5-methoxyoxazole 4y (70 mg, yield: 79%) as a yellow solid after flash column chromatography on silica gel (eluent: EtOAc/n-hexane = 1/5). Mp 101−102 °C; IR (film) νmax 3077, 2956, 2926, 2853, 1633, 1602, 1513, 1450, 1381, 1334, 1216, 1174, 1109, 1024, 966, 854 cm−1; 1H NMR (500 MHz, CDCl3) δ 0.98−1.09 (m, 7H), 1.09−1.31 (m, 4H), 1.45−1.53 (m, 1H), 1.58 (s, br, 1H), 1.62−1.80 (m, 4H), 1.92−1.99 (m, 1 H), 2.70 (hept, J = 6.2 9699

DOI: 10.1021/acs.joc.7b01768 J. Org. Chem. 2017, 82, 9693−9703

Article

The Journal of Organic Chemistry

CDCl3) δ 28.1, 28.3, 39.4, 42.5, 53.3, 60.4, 68.9, 81.4, 123.5 (2C), 127.5 (2C), 146.3, 147.3, 160.5, 172.9; HRMS-ESI calcd for [C16H19N3O4 + H]+ (M + H)+: 318.1448; found: 318.1447. Methyl Methyl-1-(4-nitrophenyl)-5,6,7,7a-tetrahydro-1H-pyrrolo[1,2-c]imidazole-1-carboxylate (5c). Following general procedure B, the reaction of 5-methylpyrrolidin-2-one (20 mg, 0.2 mmol) with Cp2ZrHCl (83 mg, 0.32 mmol), ZnCl2 (40 μL, 1.0 M in Et2O, 0.04 mmol), 2-isocyano-2-(4-nitrophenyl)acetate 3a (53 mg, 0.24 mmol), and Et3N (56 μL, 0.4 mmol) afforded 2-imidazoline 5c (57 mg, yield: 94%) as a single diastereomer after flash column chromatography on silica gel (eluent: EtOAc/n-hexane = 15/1). white solid; mp 125−127 °C; IR (film) νmax 3078, 2958, 2924, 2863, 1733, 1684, 1585, 1521, 1348, 1214, 854 cm−1; 1H NMR (400 MHz, CDCl3) δ 0.67−0.81 (m, 1H), 1.26 (d, J = 6.5 Hz, 3H), 1.34−1.52 (m, 2H), 1.95−2.08 (m, 1H), 3.65−3.80 (m, 4H), 4.84 (dd, J = 10.5, 5.6 Hz, 1H), 7.08 (s, 1H), 7.65−7.72 (m, 2H), 8.16−8.24 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 22.9, 28.4, 33.4, 53.3, 54.9, 68.3, 81.0, 123.4 (2C), 127.4 (2C), 146.2, 147.3, 160.1, 172.9; HRMS-ESI calcd for [C15H17N3O4 + Na]+ (M + Na)+: 326.1111; found: 326.1109. Methyl 6-((tert-Butyldimethylsilyl)oxy)-1-(4-nitrophenyl)-5,6,7,7atetrahydro-1H-pyrrolo[1,2-c]imidazole-1-carboxylate (5d). Following general procedure B, the reaction of (S)-4-((tertbutyldimethylsilyl)oxy)pyrrolidin-2-one (43 mg, 0.2 mmol) with Cp2ZrHCl (83 mg, 0.32 mmol), ZnCl2 (40 μL, 1.0 M in Et2O, 0.04 mmol), 2-isocyano-2-(4-nitrophenyl)acetate 3a (53 mg, 0.24 mmol), and Et3N (56 μL, 0.4 mmol) afforded 2-imidazoline 5d (60 mg, yield: 71%) as a separable mixture (dr: 2.0:1.0) after flash column chromatography on silica gel (eluent: EtOAc). Major, white solid; mp 83−84 °C; IR (film) νmax 3033, 2953, 2928, 2855, 1732, 1589, 1523, 1463, 1433, 1348, 1254, 1224, 1102, 1017, 937, 836 cm−1; 1H NMR (500 MHz, CDCl3) δ 0.00 (s, 3H), 0.01 (s, 3H), 0.82 (ddd, J = 13.0, 11.1, 5.5 Hz, 1H), 0.86 (s, 9H), 1.27 (ddd, J = 13.0, 5.7, 5.7 Hz, 1H), 3.16 (dd, J = 11.9, 1.5 Hz, 1H), 3.68 (dd, J = 11.9, 5.5 Hz, 1H), 3.72 (s, 3H), 4.24−4.28 (m, 1H), 5.03 (dd, J = 11.1, 5.7 Hz, 1H), 6.99 (s, 1H), 7.67−7.72 (m, 2H), 8.19−8.23 (m, 2H); 13C NMR (125 MHz, CDCl3) δ −5.0, −4.9, 17.9, 25.7 (3C), 37.7, 53.3, 56.9, 67.9, 71.3, 81.0, 123.5 (2C), 127.5 (2C), 146.2, 147.4, 160.4, 172.7; HRMSESI calcd for [C20H29N3O5Si + Na]+ (M + Na)+: 442.1769; found: 442.1772; [α]D25 = +296.8 (c 1.0, CHCl3). minor, colorless oil; IR (film) νmax 3039, 2954, 2928, 2855, 1732, 1699, 1592, 1522, 1471, 1347, 1257, 1095, 1074, 1022, 853, 836, 777 cm−1; 1H NMR (500 MHz, CDCl3) δ 0.06 (s, 3H), 0.08 (s, 3H), 0.88 (s, 9H), 1.52 (ddd, J = 12.9, 10.9, 5.4 Hz, 1H), 2.03 (dd, J = 12.9, 5.5 Hz, 1H), 3.07 (dd, J = 11.8, 1.1 Hz, 1H), 3.70 (dd, J = 11.8, 5.5 Hz, 1H), 3.76 (s, 3H), 4.37 (dd, J = 10.9, 5.5 Hz, 1H), 4.44−4.48 (m, 1H), 7.00 (s, 1H), 7.81− 7.84 (m, 2H), 8.18−8.22 (m, 2H); 13C NMR (125 MHz, CDCl3) δ −4.9, −4.8, 18.0, 25.7 (3C), 38.4, 52.8, 56.8, 71.2, 72.1, 81.3, 123.5 (2C), 127.3 (2C), 147.6, 149.0, 160.4, 171.1; HRMS-ESI calcd for [C20H29N3O5Si + Na]+ (M + Na)+: 442.1769; found: 442.1773; [α]D25 = +203.6 (c 1.0, CHCl3). Dimethyl 1-(4-Nitrophenyl)-5,6,7,7a-tetrahydro-1H-pyrrolo[1,2c]imidazole-1,5-dicarboxylate (5e). Following general procedure B, the reaction of methyl (R)-5-oxopyrrolidine-2-carboxylate (29 mg, 0.2 mmol) with Cp2ZrHCl (83 mg, 0.32 mmol), ZnCl2 (40 μL, 1.0 M in Et2O, 0.04 mmol), 2-isocyano-2-(4-nitrophenyl)acetate 3a (53 mg, 0.24 mmol), and Et3N (56 μL, 0.4 mmol) afforded 2-imidazoline 5e (47 mg, yield: 68%) as a separable mixture (dr: 2.4:1.0) after flash column chromatography on silica gel (eluent: EtOAc/n-hexane = 10/ 1). Major, white solid; mp 87−88 °C. IR (film) νmax 3065, 2954, 2917, 2851, 1746, 1594, 1520, 1437, 1348, 1282, 1214, 1162, 1070, 853 cm−1; 1H NMR (400 MHz, CDCl3) δ 0.71−0.84 (m, 1H), 1.46−1.56 (m, 1H), 1.98−2.11 (m, 1H), 2.14−2.24 (m, 1H), 3.72 (s, 3H), 3.78 (s, 3H), 4.24 (t, J = 8.0 Hz, 1H), 4.97 (dd, J = 10.7, 5.9 Hz, 1H), 7.12 (s, 1H), 7.67−7.73 (m, 2H), 8.19−8.24 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 27.9, 29.1, 52.5, 53.4, 59.8, 69.3, 81.1, 123.6 (2C), 127.4 (2C), 145.7, 147.4, 159.1, 172.0, 172.3; HRMS-ESI calcd for [C16H17N3O6 + Na]+ (M + Na)+: 370.1010; found: 370.1007; [α]D25 = −368.9 (c 1.0, CHCl3). Minor, colorless oil; IR (film) νmax 3068, 2954, 2853, 1734, 1592, 1521, 1436, 1350, 1284, 1244, 1209, 1166, 1108, 1027, 854, 793, 737 cm−1; 1H NMR (500 MHz, CDCl3) δ

Hz, 1H), 3.58 (d, J = 6.9 Hz, 1H), 4.14 (s, 3H), 7.90−7.95 (m, 2H), 8.19−8.23 (m, 2H); 13C NMR (125 MHz, CDCl3) δ 22.1, 23.9, 26.0, 26.1, 26.3, 29.4, 29.9, 42.5, 46.9, 59.6, 59.9, 111.7, 123.9 (2C), 124.9 (2C), 138.4, 145.4, 155.9, 156.7; HRMS-ESI calcd for [C20H27N3O4 + Na]+ (M + Na)+: 396.1894; found: 396.1893. N-(Cyclohexyl(5-methoxy-4-(4-nitrophenyl)oxazol-2-yl)methyl)cyclohexanamine (4z). Following general procedure A, the reaction of the N-cyclohexylcyclohexanecarboxamide 1z (34 mg, 0.2 mmol) with Cp2ZrHCl (114 mg, 0.44 mmol), ZnCl2 (40 μL, 1.0 M in Et2O, 0.04 mmol), 2-isocyano-2-(4-nitrophenyl)acetate 3a (53 mg, 0.24 mmol), and Et3N (56 μL, 0.4 mmol) afforded 5-methoxyoxazole 4z (60 mg, yield: 73%) as a yellow solid after flash column chromatography on silica gel (eluent: EtOAc/n-hexane = 1/5). Mp 120−122 °C; IR (film) νmax 3078, 2926, 2852, 1633, 1602, 1513, 1450, 1381, 1334, 1215, 1175, 1109, 1024, 967, 854, 733 cm−1; 1H NMR (500 MHz, CDCl3) δ 0.99−1.31 (m, 10H), 1.44−1.51 (m, 1H), 1.51− 1.61 (m, 2H), 1.61−1.80 (m, 7H), 1.89−1.99 (m, 2H), 2.29−2.37 (m, 1H), 3.61 (d, J = 7.0 Hz, 1H), 4.15 (s, 3H), 7.90−7.95 (m, 2H), 8.19− 8.24 (m, 2H); 13C NMR (125 MHz, CDCl3) δ 24.5, 24.9, 26.0 (2C), 26.1, 26.3, 29.5, 29.9, 32.8, 34.3, 42.6, 54.9, 59.4, 59.6, 111.7, 123.9 (2C), 124.9 (2C), 138.4, 145.3, 155.9, 156.9; HRMS-ESI calcd for [C23H31N3O4 + Na]+ (M + Na)+: 436.2207; found: 436.2207. Methyl 1-(4-Nitrophenyl)-5,6,7,7a-tetrahydro-1H-pyrrolo[1,2-c]imidazole-1-carboxylate (5a). Following general procedure B, the reaction of pyrrolidin-2-one (17 mg, 0.2 mmol) with Cp2ZrHCl (83 mg, 0.32 mmol), ZnCl2 (40 μL, 1.0 M in Et2O, 0.04 mmol), 2isocyano-2-(4-nitrophenyl)acetate 3a (53 mg, 0.24 mmol), and Et3N (56 μL, 0.4 mmol) afforded 2-imidazoline 5a (55 mg, yield: 85%) as a separable mixture (dr: 3.0:1.0) after flash column chromatography on silica gel (eluent: EtOAc/n-hexane = 15/1). Major, colorless oil; IR (film) νmax 3036, 2954, 2892, 1732, 1684, 1586, 1520, 1435, 1349, 1237, 1212, 1109, 1029, 854, 792 cm−1; 1H NMR (400 MHz, CDCl3) δ 0.65−0.79 (m, 1H), 1.32−1.44 (m, 1H), 1.74−1.87 (m, 2H), 3.24− 3.34 (m, 1H), 3.38−3.49 (m, 1H), 3.72 (s, 3H), 4.75 (dd, J = 10.1, 6.3 Hz, 1H), 7.06 (s, 1H), 7.65−7.73 (m, 2H), 8.17−8.25 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 24.5, 27.1, 46.7, 53.3, 69.2, 81.1, 123.5 (2C), 127.4 (2C), 146.3, 147.3, 160.8, 172.8; HRMS-ESI calcd for [C14H15N3O4 + Na]+ (M + Na)+: 312.0955; found: 312.0952. Minor, colorless oil; IR (film) νmax 3074, 2955, 2923, 2852, 1747, 1683, 1590, 1520, 1436, 1348, 1260, 1070, 853 cm−1; 1H NMR (500 MHz, CDCl3) δ 1.40−1.50 (m, 1H), 1.84−1.95 (m, 1H), 1.96−2.06 (m, 1H), 2.06−2.14 (m, 1H), 3.16−3.23 (m, 1H), 3.41−3.49 (m, 1H), 3.76 (s, 3H), 4.07 (dd, J = 10.1, 6.0 Hz, 1H), 7.04 (s, 1H), 7.80−7.85 (m, 2H), 8.17−8.21 (m, 2H); 13C NMR (125 MHz, CDCl3) δ 25.1, 28.0, 46.6, 52.8, 72.9, 81.6, 123.5 (2C), 127.4 (2C), 147.6, 149.2, 160.8, 171.2; HRMS-ESI calcd for [C14H15N3O4 + Na]+ (M + Na)+: 312.0955; found: 312.0952. Methyl 6,6-Dimethyl-1-(4-nitrophenyl)-5,6,7,7a-tetrahydro-1Hpyrrolo[1,2-c]imidazole-1-carboxylate (5b). Following general procedure B, the reaction of 4,4-dimethylpyrrolidin-2-one (23 mg, 0.2 mmol) with Cp2ZrHCl (83 mg, 0.32 mmol), ZnCl2 (40 μL, 1.0 M in Et2O, 0.04 mmol), 2-isocyano-2-(4-nitrophenyl)acetate 3a (53 mg, 0.24 mmol), and Et3N (56 μL, 0.4 mmol) afforded 2-imidazoline 5b (62 mg, yield: 98%) as a separable mixture (dr: 4.0:1.0) after flash column chromatography on silica gel (eluent: EtOAc). Major, colorless oil; IR (film) νmax 3033, 2957, 2921, 2863, 1731, 1682, 1586, 1521, 1464, 1434, 1348, 1231, 1131, 853, 795 cm−1; 1H NMR (500 MHz, CDCl3) δ 1.15 (s, 3H), 1.16 (s, 3H), 1.43 (dd, J = 12.4, 10.7 Hz, 1H), 1.88 (dd, J = 12.4, 5.9 Hz, 1H), 2.97 (d, J = 10.9 Hz, 1H), 3.16 (d, J = 10.9 Hz, 1H), 3.76 (s, 3H), 4.25 (dd, J = 10.7, 5.9 Hz, 1H), 7.06 (s, 1H), 7.80−7.83 (m, 2H), 8.17−8.21 (m, 2H); 13C NMR (125 MHz, CDCl3) δ 28.3, 28.5, 40.1, 43.4, 52.8, 60.4, 72.7, 81.8, 123.5 (2C), 127.3 (2C), 147.6, 149.3, 160.6, 171.1; HRMS-ESI calcd for [C16H19N3O4 + H]+ (M + H)+: 318.1448; found: 318.1446. Minor, colorless oil; IR (film) νmax 3033, 2956, 2917, 2849, 1729, 1591, 1520, 1386, 1347, 1259, 1196, 1131, 1075, 853 cm−1; 1H NMR (500 MHz, CDCl3) δ 0.69 (dd, J = 12.4, 10.7 Hz, 1H), 0.97 (s, 3H), 1.14 (s, 3H), 1.17 (dd, J = 12.4, 6.3 Hz, 1H), 3.06 (d, J = 12.9 Hz, 1H), 3.14 (d, J = 12.9 Hz, 1H), 3.71 (s, 3H), 4.96 (dd, J = 10.7, 6.3 Hz, 1H), 7.05 (s, 1H), 7.66−7.70 (m, 2H), 8.19−8.23 (m, 2H); 13C NMR (125 MHz, 9700

DOI: 10.1021/acs.joc.7b01768 J. Org. Chem. 2017, 82, 9693−9703

Article

The Journal of Organic Chemistry

1280, 1237, 1132, 1111, 1022, 859, 773 cm−1; 1H NMR (500 MHz, CDCl3) δ 0.69−0.79 (m, 1H), 1.31−1.39 (m, 1H), 1.70−1.83 (m, 2H), 3.26 (ddd, J = 11.0, 8.4, 5.0 Hz, 1H), 3.41 (ddd, J = 11.0, 7.7, 7.7 Hz, 1H), 3.70 (s, 3H), 3.91 (s, 3H), 4.74 (dd, J = 10.0, 6.4 Hz, 1H), 7.01 (s, 1H), 7.53−7.58 (m, 2H), 8.00−8.04 (m, 2H); 13C NMR (125 MHz, CDCl3) δ 24.6, 27.1, 46.9, 52.1, 53.1, 69.2, 81.4, 126.4 (2C), 129.4, 129.6 (2C), 144.1, 160.6, 166.8, 173.3; HRMS-ESI calcd for [C16H18N2O4 + Na]+ (M + Na)+: 325.1159; found: 325.1157. Minor, IR (film) νmax 3033, 2954, 2917, 2849, 1722, 1666, 1593, 1434, 1407, 1385, 1280, 1132, 1112, 1076, 1020, 859, 780 cm−1; 1H NMR (500 MHz, CDCl3) δ 1.38−1.48 (m, 1H), 1.81−1.92 (m, 1H), 1.94−2.04 (m, 1H), 2.04−2.12 (m, 1H), 3.18 (ddd, J = 11.0, 9.4, 4.1 Hz, 1H), 3.43 (ddd, J = 11.0, 7.8, 7.8 Hz, 1H), 3.75 (s, 3H), 3.90 (s, 3H), 4.09 (dd, J = 10.1, 6.0 Hz, 1H), 7.01 (s, 1H), 7.68−7.72 (m, 2H), 7.98− 8.02 (m, 2H); 13C NMR (125 MHz, CDCl3) δ 25.1, 28.0, 46.5, 52.0, 52.5, 72.7, 81.7, 126.2 (2C), 129.6 (2C), 129.7, 147.0, 160.4, 166.7, 171.6; HRMS-ESI calcd for [C16H18N2O4 + Na]+ (M + Na)+: 325.1159; found: 325.1159. Methyl 1-Benzyl-4-(4-nitrophenyl)-5-pentyl-4,5-dihydro-1H-imidazole-4-carboxylate (5aa). Following general procedure A, the reaction of the N-benzylhexanamide (41 mg, 0.2 mmol) with Cp2ZrHCl (114 mg, 0.44 mmol), ZnCl2 (40 μL, 1.0 M in Et2O, 0.04 mmol), 2-isocyano-2-(4-nitrophenyl)acetate (53 mg, 0.24 mmol), and Et3N (56 μL, 0.4 mmol) afforded 5-methoxyoxazole 5aa (19 mg, yield: 23%) as an inseparable mixture (dr: 5.0:1.0) after flash column chromatography on silica gel (eluent: EtOAc/n-hexane = 6/1). IR (film) νmax 3030, 2953, 2930, 2858, 1733, 1684, 1593, 1521, 1455, 1348, 1229, 1177, 1109, 854, 700 cm−1; 1H NMR (500 MHz, CDCl3) δ 0.70 (t, J = 7.3 Hz, 6H, major+minor), 0.80−0.93 (m, 6H, major +minor), 0.93−1.05 (m, 4H, major+minor), 1.07−1.38 (m, 4H, major +minor), 1.70−1.94 (m, 2H, major+minor), 3.72 (s, 3H, major), 3.72−3.75 (m, 4H, minor), 4.19 (d, J = 15.5 Hz, 1H, minor), 4.22 (d, J = 15.4 Hz, 1H, major), 4.40 (dd, J = 6.2, 4.2 Hz, 1H, major), 4.49 (d, J = 15.5 Hz, 1H, minor), 4.53 (d, J = 15.4 Hz, 1H, major), 7.00−7.05 (m, 2H, minor), 7.18 (s, 2H, major+minor), 7.21−7.24 (m, 3H, minor), 7.23−7.28 (m, 2H, major), 7.31−7.36 (m, 1H, major), 7.36− 7.42 (m, 2H, major), 7.52−7.58 (m, 2H, major), 7.70−7.74 (m, 2H, minor), 8.12−8.16 (m, 2H, minor), 8.17−8.22 (m, 2H, major); 13C NMR (125 MHz, CDCl3) δ 13.7 (major), 13.9 (minor), 22.1 (major), 22.4 (minor), 24.2 (major), 25.3 (minor), 28.8 (major), 29.9 (minor), 31.6 (major), 32.0 (minor), 49.3 (minor), 49.4 (major), 52.7 (minor), 53.2 (major), 63.9 (major), 68.3 (minor), 82.2 (minnor), 83.2 (major), 123.1 (2C, major), 123.1 (2C, minor), 127.3 (2C, minor), 127.6 (2C, major), 127.7 (2C, minor), 128.0 (minor), 128.0 (major), 128.4 (2C, major), 128.8 (2C, minor), 128.9 (2C, major), 135.9 (major), 135.9 (minor), 145.2 (major), 145.2 (minor), 147.2 (minor), 147.3 (major), 156.9, (minor), 156.9 (major), 171.3 (minor), 173.3 (major); HRMS-ESI calcd for [C23H27N3O4 + H]+ (M + H)+: 410.2074; found: 410.2075.

1.45−1.56 (m, 1H), 2.05−2.16 (m, 1H), 2.20−2.27 (m, 1H), 2.34− 2.43 (m, 1H), 3.72 (s, 3H), 3.76 (s, 3H), 4.26 (t, J = 8.0 Hz, 1H), 4.32 (dd, J = 10.5, 5.7 Hz, 1H), 7.10 (s, 1H), 7.79−7.83 (m, 2H), 8.17− 8.22 (m, 2H); 13C NMR (125 MHz, CDCl3) δ 28.8, 29.8, 52.5, 52.9, 59.6, 72.7, 81.6, 123.6 (2C), 127.5 (2C), 147.7, 148.6, 159.0, 170.8, 172.2; HRMS-ESI calcd for [C16H17N3O6 + Na]+ (M + Na)+: 370.1010; found: 370.1008; [α]D25 = −158.3 (c 1.0, CHCl3). 5-tert-Butyl 1-Methyl (5S)-1-(4-nitrophenyl)-5,6,7,7a-tetrahydro1H-pyrrolo[1,2-c]imidazole-1,5-dicarboxylate (5f). Following general procedure A, the reaction of the tert-butyl (S)-5-oxopyrrolidine-2carboxylate (37 mg, 0.2 mmol) with Cp2ZrHCl (83 mg, 0.32 mmol), ZnCl2 (40 μL, 1.0 M in Et2O, 0.04 mmol), 2-isocyano-2-(4nitrophenyl)acetate 3a (53 mg, 0.24 mmol), and Et3N (56 μL, 0.4 mmol) afforded 2-imidazoline 5f (52 mg, yield: 66%) as a colorless oil after flash column chromatography on silica gel (eluent: EtOAc/nhexane = 6/1).; IR (film) νmax 3071, 2977, 2949, 2927, 2869, 1735, 1677, 1592, 1522, 1457, 1368, 1349, 1287, 1242, 1222, 1155, 1108, 1030, 854, 794 cm−1; 1H NMR (500 MHz, CDCl3) δ 0.70−0.80 (m, 1H), 1.44−1.47 (m, 1H), 1.49 (s, 9H), 1.90−1.99 (m, 1H), 2.11−2.20 (m, 1H), 3.72 (s, 3H), 4.12 (t, J = 7.9 Hz, 1H), 4.97 (dd, J = 10.6, 6.0 Hz, 1H), 7.10 (s, 1H), 7.68−7.73 (m, 2H), 8.18−8.23 (m, 2H); 13C NMR (125 MHz, CDCl3) δ 27.8, 27.9 (3C), 29.3, 53.4, 60.6, 69.4, 81.1, 82.0, 123.5 (2C), 127.4 (2C), 145.9, 147.4, 159.2, 170.8, 172.3; HRMS-ESI calcd for [C19H23N3O6 + Na]+ (M + Na)+: 412.1479; found: 412.1477. [α]D20 = −286.8 (c 1.0, CHCl3). Methyl 3-(4-Nitrophenyl)-3,3a,4,5-tetrahydroimidazo[1,5-a]quinoline-3-carboxylate (5g). Following general procedure B, the reaction of 3,4-dihydroquinolin-2(1H)-one (29 mg, 0.2 mmol) with Cp2ZrHCl (83 mg, 0.32 mmol), ZnCl2 (40 μL, 1.0 M in Et2O, 0.04 mmol), 2-isocyano-2-(4-nitrophenyl)acetate 3a (53 mg, 0.24 mmol), and Et3N (56 μL, 0.4 mmol) afforded 2-imidazoline 5g (20 mg, yield: 28%) as a single diastereomer after flash column chromatography on silica gel (eluent: EtOAc/n-hexane = 2/1). Colorless oil; IR (film) νmax 3039, 2951, 2924, 2853, 1732, 1591, 1576, 1519, 1497, 1459, 1435, 1348, 1252, 1224, 1107, 854, 744 cm−1; 1H NMR (400 MHz, CDCl3) δ 0.79−0.92 (m, 1H), 1.41−1.50 (m, 1H), 2.69−2.78 (m, 1H), 2.85− 2.98 (m, 1H), 3.80 (s, 3H), 4.87 (dd, J = 12.5, 2.8 Hz, 1H), 6.92−6.99 (m, 1H), 7.05−7.13 (m, 2H), 7.13−7.20 (m, 1H), 7.54−7.60 (m, 2H), 7.67 (s, 1H), 8.20−8.26 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 24.0, 27.0, 53.5, 61.8, 82.5, 115.4, 122.8, 123.5 (2C), 123.9, 127.3, 127.8 (2C), 129.8, 135.9, 144.7, 147.6, 151.9, 172.6; HRMS-ESI calcd for [C19H17N3O4 + Na]+ (M + Na)+: 374.1111; found: 374.1112. 5-tert-Butyl 1-Methyl (1S,5S,8aS)-1-(4-Nitrophenyl)-1,5,6,7,8,8ahexahydroimidazo[1,5-a]pyridine-1,5-dicarboxylate (5h). Following general procedure B, the reaction of tert-butyl (S)-6-oxopiperidine-2carboxylate (40 mg, 0.2 mmol) with Cp2ZrHCl (83 mg, 0.32 mmol), ZnCl2 (40 μL, 1.0 M in Et2O, 0.04 mmol), 2-isocyano-2-(4nitrophenyl)acetate 3a (53 mg, 0.24 mmol), and Et3N (56 μL, 0.4 mmol) afforded 2-imidazoline 5h (18 mg, yield: 22%) as a colorless oil after flash column chromatography on silica gel (eluent: EtOAc/nhexane = 7/1). IR (film) νmax 3071, 2975, 2949, 2931, 2859, 1732, 1677, 1586, 1522, 1445, 1348, 1298, 1232, 1152, 1109, 1023, 999, 913, 854 cm−1; 1H NMR (500 MHz, CDCl3) δ 0.40−0.50 (m, 1H), 1.29− 1.35 (m, 1H), 1.43−1.49 (m, 2H), 1.51 (s, 9H), 1.65−1.71 (m, 1H), 2.09−2.14 (m, 1H), 3.75 (s, 3H), 4.23−4.27 (m, 1H), 4.58 (dd, J = 12.3, 3.5 Hz, 1H), 7.12 (s, 1H), 7.50−7.55 (m, 2H), 8.17−8.22 (m, 2H); 13C NMR (125 MHz, CDCl3) δ 20.5, 27.0 (2C), 28.0 (3C), 53.1, 56.1, 61.1, 81.7, 82.5, 123.3 (2C), 127.8 (2C), 144.9, 147.4, 155.6, 169.7, 172.8; HRMS-ESI calcd for [C20H25N3O6 + H]+ (M + H)+: 404.1816; found: 404.1819; [α]D25 = −113.5 (c 1.0, CHCl3). We were unable to isolate other isomers in pure form. Methyl 1-(4-(Methoxycarbonyl)phenyl)-5,6,7,7a-tetrahydro-1Hpyrrolo[1,2-c]imidazole-1-carboxylate (5j). Following general procedure B, the reaction of pyrrolidin-2-one (17 mg, 0.2 mmol) with Cp2ZrHCl (83 mg, 0.32 mmol), ZnCl2 (40 μL, 1.0 M in Et2O, 0.04 mmol), methyl 4-(2-methoxy-1-nitro-2-oxoethyl)benzoate 3b (47 mg, 0.24 mmol), and Et3N (56 μL, 0.4 mmol) afforded 2-imidazoline 5j (27 mg, yield: 45%) as a separable mixture (dr: 1.7:1.0) after flash column chromatography on silica gel (eluent: EtOAc). Major, IR (film) νmax 3030, 2953, 2917, 2849, 1723, 1591, 1435, 1408, 1385,

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.7b01768. 1 H NMR and 13C NMR spectra of all products and the ORTEP diagram and crystallographic data for compound 5c (PDF) X-ray data for compound 5c (CIF)

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Pei-Qiang Huang: 0000-0003-3230-0457 Notes

The authors declare no competing financial interest. 9701

DOI: 10.1021/acs.joc.7b01768 J. Org. Chem. 2017, 82, 9693−9703

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ACKNOWLEDGMENTS The authors are grateful for financial support from the National Natural Science Foundation of China (21672177, 21332007), Natural Science Foundation of Fujian Province of China (2016J01074), Chinese Universities Scientific Fund (20720150048), NFFTBS (J1310024), and the Program for Changjiang Scholars and Innovative Research Team in University (PCSIRT) of the Ministry of Education, China. We thank the reviewers for the valuable comments and suggestions on several aspects of the manuscript including the mechanisms.

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