Cascade reaction of MoritaâBaylisâHillman acetates with 1,1

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Cascade reaction of Morita–Baylis–Hillman acetates with 1,1-enediamines or heterocyclic ketene aminals: Synthesis of highly functionalized 2-aminopyrroles Jin Liu, Qi Li, Zheng-Mao Cao, Yi Jin, Jun Lin, and Sheng-Jiao Yan J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b02594 • Publication Date (Web): 21 Jan 2019 Downloaded from http://pubs.acs.org on January 21, 2019

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The Journal of Organic Chemistry

Cascade reaction of Morita–Baylis–Hillman acetates with 1,1-enediamines or heterocyclic ketene aminals: Synthesis of highly functionalized 2-aminopyrroles Jin Liu, Qi Li, Zheng-Mao Cao, Yi Jin, Jun Lin* and Sheng-Jiao Yan* Key Laboratory of Medicinal Chemistry for Natural Resource (Yunnan University), Ministry of Education, School of Chemical Science and Technology, Yunnan University, Kunming, 650091, P. R. China. KEYWORDS:

2-Aminopyrroles,

bicyclic

pyrroles,

Morita–Baylis–Hillman

acetates,

heterocyclic ketene aminals, 1,1-enediamines.

ACS Paragon Plus Environment

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ABSTRACT: A new strategy for the construction of two kinds of fully substituted pyrroles, including 2-aminopyrroles and bicyclic pyrroles from Morita–Baylis–Hillman (MBH), acetates with 1,1-enediamines (EDAMs) or heterocyclic ketene aminals (HKAs) via base-promoted tandem Michael addition, elimination, and aromatization sequence has been developed, affording the expected products in moderate to excellent yields. This methodology is a highly efficient, concise way to access 2-aminopyrroles or bicyclic pyrroles with diversity in molecular structures from accessible building blocks under moderate reaction conditions.


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

INTRODUCTION Among of the most representative aromatic heterocycles, pyrroles are embedded in a large

number of natural products, biologically important molecules, and pharmaceuticals. 1 As an important subset of pyrroles, 2-aminopyrrole is also recognized as a common medicinal building block. For example, fully substituted 2-aminopyrroles have shown a variety of pharmacological activities such as MEK inhibitor,2 MBLs inhibitor (Fig. 1),3 PDE inhibitor,4 and TNF-α production inhibitor.5 Furthermore, 2-aminopyrroles are used as precursors for the preparation of analogues of purine bases, including pyrrolopyrimidines, pyrrolopyridines, and pyrrolopyrazoles. It is noteworthy that the functionalized bicyclic pyrrole derivatives have recently received attention because of their promising biological properties. For example, phloeodictine A (Fig. 1), which was originally isolated from marine sponges, showed antimicrobial, antimalarial, and cytotoxic activities to varying degrees;6 CGP-029482 is a potent and selective protein kinase CK2 inhibitor;7 and pyrrolopyrimidine derivative also is an antagonist against CRF receptors (Fig. 1).8

Figure 1. Bioactive 2-aminopyrroles and the target compounds 4–5.


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In recent decades, a considerable amount of efforts have been devoted to the preparation of diverse substituted pyrrole derivatives.9-10 However, only a few approaches have been developed for the synthesis of 2-aminopyrroles through classical methods of pyrrole ring construction.11 The main synthetic methods of 2-aminopyrroles can be summarized as follows: (1) multicomponent reaction based on nitrile or isocyanide-containing substrates,9 and (2) cycloisomerization of alkyne and allene-containing substrates catalyzed by transition metal complexes.10 For example, Ye et al. recently reported a gold-catalyzed intermolecular alkyne amination-initiated cyclization to afford various 2-aminopyrroles (Scheme 1).12 Zhu et al. reported a [4+1] cycloaddion of 2-cyano-1-azadienes (formation through an oxidative Strecker reaction) with various isocyanides to provide 2-aminopyrroles (Scheme 1).13 Despite these methods having made significate contributions to the preparation of 2-aminopyrroles, they usually present several shortcomings. For example, these shortcomings include the demand for expensive transition metal additives, stricter reaction conditions, tedious operation processes, and poor selectivity. In addition, the preparation of 2-aminopyrroles by non-nitrile (or nonisocyanide) substrates, as well as metal free methods, is very rare. Therefore, it is extremely desirable for efficient and metal-free approaches toward 2-aminopyrrole derivatives to be developed that aim at achieving diversity in molecular structures from accessible building blocks and under moderate reaction conditions. Heterocyclic ketene aminals (HKAs) are interesting and diversified building blocks that have been extensively used to construct a variety of functionalized fused heterocyclic compounds.14 Many of them have extensive pharmacological activities such as being antineoplastic,15 herbicidal, insecticidal,16 anti-anxiety,17 antileishmanial,18 and antibacterial.19 Comparatively, acyclic 1,1-enediamines (EDAMs) have not been widely concerned in the past. Some groups


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have used EDAMs to serve as bisnucleophiles and react with various electrophiles to prepare high functionalized heterocycles.20 On the other hand, Baylis and Hillman have earlier reported the synthesis of α-hydroxyethyl nitro-ethylenes from the Morita–Baylis–Hillman (MBH) reaction.21 Namboothiri and Chen then investigated the use of electrophilic ethyl glyoxalate in this reaction.22 Further acetylation on the hydroxyl groups of these conjugated nitro-ethylenes afforded MBH acetates being shown to have applicable bielectrophiles in the SN2′ addition– elimination sequence reaction with various nucleophiles, synthesizing the diversified heterocyclic molecules.23 Continuing our interest in the preparation of functionalized heterocycles with biological activity and from available building blocks,15,24 we aim to use the diverse building blocks MBH acetates and EDAMs/HKAs to construct novel 2-aminopyrrole ring systems with fully substituted 2-aminopyrroles and bicyclic pyrroles as the products (Scheme 1). Use of the N(3) of EDAMs 2 to attack the electrophilic sites of C(2) of MBH acetates 1 show little steric effects. However, the N(4) rather than N(3) of EDAMs 2 can attack the electrophilic sites C(1) of MBH acetates 1 (Scheme 1). The results may be due to the effects of intramolecular H-bonds of EDAMs 2, which make the N(4) approach the C(2) of MBH acetates 1. In addition, the intramolecular H-bond of the target compounds 4–5 is favorable to the structural stability of the compounds being the intramolecular H-bond forms a six-number ring system (Scheme 1). As a result, the nucleophilic reactivity of secondary amino N(4) of EDAMs 2 is greater than that of primary amino N(3). Using this property, various 2-amino heterocycles can be regioselectively constructed by the law of intramolecular H-bond effects, including EDAMs and other similar building blocks.


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Scheme 1. Methods for the construction of substituted 2-aminopyrrole derivatives

RESULTS AND DISCUSSION The reaction of MBH acetate 1b (1.2 mmol) and EDAMs 2a (1.0 mmol) in the presence of 1 equiv. of piperidine in CH2Cl2 under room temperature for 60 min, giving highly substituted 2aminopyrrole 4b in 26% yield. However, the reaction was still incomplete even after a long reaction time under room temperature conditions (Table 1, entry 1). With an increase in temperature to 40 ºC in CH2Cl2, the reaction gave 4b in 63% yield. (Table 1, entry 2). Several solvents (aprotic or protonic) in the presence of piperidine were screened (Table 1, entry 3–6). The results revealed that 1, 4-dioxane was the best solvent and produced the expected 2aminopyrrole 4b with 75% yield (Table 1, entry 6). The bases, which included K2CO3, N,N-


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diisopropyl

ethylamine

(DIPEA),

1,4-diazabicyclo[2.2.2]-octane

(DBACO),

and

1,8-

diazabicyclo[5,4,0]-undec-7-ene (DBU), were applied in the reaction in 1,4-dioxane for 10~120 min at 40 C (Table 1, entry 7–10). Finally, a raise in the yield (87%) with a reduction in reaction time (10 min) was observed when this reaction was carried out in the presence of 1 Table 1. Optimization of the reaction conditions for the model reactiona

a

entry

solvent

base

t (℃)

time/min

yieldb (%)

1

CH2Cl2

Piperidine

rt

60

26d

2

CH2Cl2

Piperidine

40

30

63

3

CH3CN

Piperidine

40

30

53

4

EtOH

Piperidine

40

30

56

5

Acetone

Piperidine

40

30

72

6

1,4-Dioxane

Piperidine

40

30

75

7

1,4-Dioxane

K2CO3

40

120

trace

8

1,4-Dioxane

DIPEA

40

120

trace

9

1,4-Dioxane

DBACO

40

30

44

10

1,4-Dioxane

DBU

40

10

87

11

1,4-Dioxane

DBUc

40

60

41

Reagents and conditions: MBH acetate 1b (1.2 mmol), EDAMs 2a (1.0 mmol), Base (1.0

mmol), solvent (10 mL).

b

Isolated yield based on 2a.

c

DBU (0.5 mmol).

d

Reaction

incomplete.


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equiv. of DBU (Table 1, entry 10). A longer reaction time (60 min) and substantial decrease in the yield (41%) were encountered when the quantity of DBU was decreased to 0.5 equiv. (Table 1, entry 11). Based upon the optimized reaction conditions, we set out to explore the scope and limitations of the tandem reaction involving different MBH acetates of nitroolefins 1 with the different Nsubstituted EDAMs 2 (Table 2). The results revealed that N-phenyl EDAMs and N-alkyl EDAMs can achieve higher yields than N-benzyl EDAMs (Table 2, 4a–4e, 4i–4m vs. 4f–4h). The electron-withdrawing group (F and Cl)-substituted of the MBH acetates can obtain a higher yield than the electron-donating group (MeO) of the MBH acetates (Table 2, 4a, 4b, 4e vs. 4c, 4d; 4i vs. 4k). In brief, all of the substrates could be make use of this reaction and give fully substituted 2-aminopyrroles 4 in good yields (Table 2). Only a limited amount of approaches have been developed for the synthesis of bicyclic pyrrole derivatives.1e,25 After efficaciously synthesizing 2-aminopyrroles from EDAMs, we continued to probe the scope of the tandem reaction. The six-membered ring nitro HKAs 3a were used in this reaction. Expectedly, all the MBH acetate 1 with representative variation of substituents reacted smoothly with six-membered ring nitro HKAs 3a, obtaining the corresponding bicyclic pyrroles 5a–5f in good yields (Table 3). Compared with the conditions for the preparation of fully substituted 2-aminopyrroles, this reaction can reach a fast transformation at room temperature; HKAs have better solubility than EDAMs in 1, 4-dioxane. The electron-withdrawing group (F and Cl)-substituted of the MBH acetates can achieve higher yield than the electron-donating group (MeO) of the MBH acetates (Table 3, 5a, 5b, 5f vs. 5d).


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Table 2. The synthesis of fully substituted 2-aminopyrroles 4a–4ma-b

a

Reagents and conditions: MBH acetate 1 (1.2 mmol), EDAMs 2 (1.0 mmol), DBU (1.0 mmol),

1,4-Dioxane (10 mL). b Isolated yield based on 2.


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Table 3. The synthesis of tetrahydrobicyclic pyrroles 5a–5ya-b


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a

Reagents and conditions: MBH acetate 1 (1.2 mmol), HKA 3 (1.0 mmol), DBU (1.0 mmol),

1,4-Dioxane (10 mL). b Isolated yield based on 3.

The reaction scope was further extended to the different benzoyl-substituted HKAs 3. The results showed that the electron-withdrawing group (F and Cl)-substituted benzoyl HKAs can reach higher yield than the electron-donating group (Me and MeO) HKAs (Table 3, 5i, 5j, 5o vs. 5n; 5p vs. 5r; 5w vs. 5r). The substituted group of the MBH acetates 1 follows the same rule; the electron-withdrawing group (F, Cl, Br) benefits the yield of the reaction (Table 3, 5m vs. 5r; 5h vs. 5q). In brief, all of the substrates could make use of the reaction and give compounds 5 in good yields (Table 3, 5a–5y). To confirm the structure of the fully substituted 2-aminopyrroles and bicyclic pyrrole derivatives, 4a and 5c were chosen as the typical compounds and were characterized by X-ray crystallography, as shown in Figure S1 and Figure S2 (See Supporting Information). Based on the above experimental data and the known literature precedents,26 the proposed mechanism taking EDAMs 2 as the illustration is outlined in Scheme 2. The α-C of EDAMs 2 initiates the nucleophilic Michael addition to MBH acetates 1, followed by the elimination of the acetate group by a SN2' pathway to generate intermediate 7. Based on the imine-enamine tautomerization of 7, further intramolecular aza-Michael addition involving the secondary amine in a 5-exo-trig fashion results in a cyclization of intermediate 8 promoted by base. Subsequent aromatization by elimination of HNO2 is then finally thought to yield fully substituted 2aminopyrroles 4. It is worth noting that the primary amine group as a donor and ortho-positions nitro group of intermediate 7 and 8 form intramolecular hydrogen bonding, which may play a vital role in the course of the regioselective preparation of fully substituted 2-aminopyrroles 4 (Scheme 2). Further, it also went through a similar mechanism process to afford functionalized


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bicyclic pyrroles 5. Scheme 2. Proposed Mechanism for the formation of fully substituted 2-aminopyrroles



CONCLUSIONS We have developed a practical strategy for the preparation of highly functionalized 2-

aminopyrroles and bicyclic pyrroles via a base-promoted tandem reaction between MBH Acetates and EDAMs/HKAs. This reaction provides a novel, rapid, and efficient route for the preparation of a variety of bicyclic pyrroles and fully substituted 2-aminopyrroles in good yields from readily accessible building blocks. Moreover, those series of highly functionalized bicyclic pyrroles and 2-aminopyrroles could offer potentially pharmacological activities for medical treatment. Our future investigations will assess the in vitro pharmacological activities of highly functionalized pyrroles 4–5. 

EXPERIMENTAL SECTION General Methods. All compounds were fully characterised by spectroscopic data. The NMR

spectra were recorded on a Bruker Ascend III 600 (1H: 600 MHz,

13

C: 150 MHz) or Bruker

DRX500 (1H: 500 MHz, 13C: 125 MHz). Chemical shifts (δ) are expressed in ppm and J values


12

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are given in Hz. Deuterated DMSO-d6 was used as solvents. IR spectra were recorded on a FTIR Thermo Nicolet Avatar 360 using a KBr pellet. The reactions were monitored by thin layer chromatography (TLC) using silica gel GF254. The melting points were determined on a XT-4A melting point apparatus and are uncorrected. HRMs were performed on an Agilent LC/Msd TOF instrument. Column chromatography was performed on silica gel (200–300 mesh). X-ray diffraction was obtained by APEX DUO. All of the MBH acetates of nitroolefins22b,27 1, acyclic 1,1-enediamines (EDAMs)28 2 and heterocyclic ketene aminals (HKAs)29 3 were synthesized by known literature procedures. All the other chemicals used in the experiment were purchased from commercial sources and were used without further purification. General procedure for the synthesis of fully substituted 2-aminopyrroles 4. MBH acetate 1 (1.2 mmol), EDAM derivative 2 (1.0 mmol) and dioxane (10 mL) were placed into a 25 mL round-bottom flask and the mixture was heated at 40℃, then DBU (1.0 mmol) was added and the mixture was stirred at 40℃ until the completion of the reaction was monitored by TLC (about 10 min). The reaction mixture was extracted with dichloromethane (3×10 mL), washed with water and brine, respectively, and dried over Na2SO4. The combined organic phases were evaporated under reduced pressure to afford the crude product. Finally, the product was obtained in pure form through column chromatography over silica gel using a mixture of petroleum ether/ethyl acetate (2:1, v/v) as the eluent. 2-(5-Amino-1,3-bis(4-fluorophenyl)-4-nitro-1H-pyrrol-2-yl) ethyl acetate (4a). Yield: 360 mg (90%), light yellow solid: mp 193.5–194.5 C; IR (KBr): 3400, 3273, 1724, 1635, 1509, 1420, 1304, 1218, 1155, 1035, 840, 537 cm-1; 1H NMR (600 MHz, CDCl3): δ = 7.40–7.05 (m, 8H, PhH), 5.92 (br, 2H, NH2), 4.00–3.97 (m, 2H, OCH2), 3.18 (s, 2H, CH2), 1.13–1.11 (m, 3H, CH3); 13

C{1H} NMR (150 MHz, CDCl3): δ = 169.8, 163.3 (d, 1JCF = 250.5 Hz), 162.3 (d, 1JCF = 244.5


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Hz), 144.3, 131.8, 130.8, 129.1, 128.2, 119.3, 117.6 (d, 2JCF = 22.5 Hz), 117.4, 116.5, 114.9 (d, 2

JCF = 22.5 Hz), 61.3, 30.5, 14.0; HRMS (TOF ESI+): m/z calcd for C20H18O4N3F2 [M+H]+,

402.1260; found, 402.1260. 2-(5-Amino-3-(4-chlorophenyl)-1-(4-fluorophenyl)-4-nitro-1H-pyrrol-2-yl) ethyl acetate (4b). Yield: 362 mg (87%), light yellow solid: mp 173–173.5 C; IR (KBr): 3402, 3283, 3157, 1731, 1635, 1420, 1355, 1219, 1155, 1024, 830, 537 cm-1; 1H NMR (500 MHz, CDCl3): δ = 7.40–7.24 (m, 8H, PhH), 5.93 (br, 2H, NH2), 4.01–3.97 (m, 2H, OCH2), 3.17 (s, 2H, CH2), 1.13–1.11 (m, 3H, CH3); 13C{1H} NMR (125 MHz, CDCl3): δ = 169.8, 163.3 (d, 1JCF = 250.0 Hz), 144.4, 133.4, 131.5, 130.8, 129.0, 128.1, 119.3, 117.6 (d, 2JCF = 22.5 Hz), 117.2, 116.3, 61.3, 30.5, 14.0; HRMS (TOF ESI+): m/z calcd for C20H18O4N3ClF [M+H]+, 418.0965; found, 418.0964. 2-(5-Amino-1-(4-fluorophenyl)-3-(4-methoxyphenyl)-4-nitro-1H-pyrrol-2-yl) ethyl acetate (4c). Yield: 346 mg (84%), light yellow solid: mp 193.5–195 C; IR (KBr): 3418, 3286, 1733, 1625, 1512, 1416, 1246, 1143, 1032, 832, 531 cm-1; 1H NMR (500 MHz, CDCl3): δ = 7.40–6.90 (m, 8H, PhH), 5.92 (br, 2H, NH2), 4.00–3.96 (m, 2H, OCH2), 3.83 (s, 3H, OCH3) 3.19 (s, 2H, CH2), 1.13–1.10 (m, 3H, CH3);

13

C{1H} NMR (125 MHz, CDCl3): δ = 170.0, 163.3 (d, 1JCF = 251.3

Hz), 144.3, 131.3, 130.8, 129.3, 124.4, 119.0, 118.0, 117.6 (d, 2JCF = 23.8 Hz), 116.6, 113.4, 61.2, 55.2, 30.6, 14.1; HRMS (TOF ESI+): m/z calcd for C21H21O5N3F [M+H]+, 414.1460; found, 414.1464. 2-(5-Amino-3-(4-methoxyphenyl)-4-nitro-1-(p-tolyl)-1H-pyrrol-2-yl) ethyl acetate (4d). Yield: 330 mg (81%), light yellow solid: mp 170.5–171 C; IR (KBr): 3421, 3297, 2932, 1733, 1623, 1512, 1410, 1245, 1146, 1034, 827, 523 cm-1; 1H NMR (500 MHz, CDCl3): δ = 7.36–6.90 (m, 8H, PhH), 5.92 (br, 2H, NH2), 4.00–3.96 (m, 2H, OCH2), 3.82 (s, 3H, OCH3) 3.20 (s, 2H, CH2), 2.44 (s, 3H, PhCH3) 1.12–1.09 (m, 3H, CH3);

13

C{1H} NMR (125 MHz, CDCl3): δ = 170.1,


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158.9, 144.3, 140.6, 131.3, 131.1, 130.6, 128.3, 124.7, 119.2, 117.7, 116.6, 113.4, 61.0, 55.2, 30.7, 21.3, 14.1; HRMS (TOF ESI+): m/z calcd for C22H23O5N3Na [M+Na]+, 432.1530; found, 432.1535. 2-(5-Amino-3-(2,4-dichlorophenyl)-1-(4-fluorophenyl)-4-nitro-1H-pyrrol-2-yl) ethyl acetate (4e). Yield: 387 mg (86%), light yellow solid: mp 123–123.5 C; IR (KBr): 3426, 3309, 2983, 1731, 1632, 1424, 1307, 1222, 1156, 1024, 855, 537 cm-1; 1H NMR (600 MHz, CDCl3): δ = 7.48–7.26 (m, 7H, PhH), 5.89 (br, 2H, NH2), 3.97–3.94 (m, 2H, OCH2), 3.12 (s, 2H, CH2), 1.12– 1.09 (m, 3H, CH3);

13

C{1H} NMR (150 MHz, CDCl3): δ = 169.2, 163.4 (d, 1JCF = 250.5 Hz),

143.9, 136.1, 134.3, 132.6, 130.8, 130.4, 129.2, 129.0, 126.8, 119.4, 117.7 (d, 2JCF = 22.5 Hz), 116.8, 114.4, 61.3, 30.4, 14.0; HRMS (TOF ESI+): m/z calcd for C20H17O4N3Cl2F [M+H]+, 452.0575; found, 452.0571. 2-(5-Amino-1-(4-chlorobenzyl)-3-(4-fluorophenyl)-4-nitro-1H-pyrrol-2-yl) ethyl acetate (4f). Yield: 335 mg (78%), light yellow solid: mp 148.5–149.5 C; IR (KBr): 3423, 3302, 2981, 1743, 1631, 1491, 1414, 1234, 843, cm-1; 1H NMR (500 MHz, CDCl3): δ = 7.36–7.04 (m, 8H, PhH), 6.11 (br, 2H, NH2), 5.01 (s, 2H, PhCH2), 4.05–4.01 (m, 2H, OCH2), 3.32 (s, 2H, CH2), 1.20–1.17 (m, 3H, CH3); 13C{1H} NMR (125 MHz, CDCl3): δ = 169.8, 162.3 (d, 1JCF = 245.0 Hz), 144.2, 134.4, 132.7, 132.0, 129.5, 128.2, 127.4, 118.9, 117.4, 116.8, 114.8(d, 2JCF = 21.3 Hz), 61.6, 45.9, 30.5, 14.0; HRMS (TOF ESI+): m/z calcd for C21H20O4N3ClF [M+H]+, 432.1121; found, 432.1123. 2-(5-Amino-1-benzyl-3-(4-chlorophenyl)-4-nitro-1H-pyrrol-2-yl) ethyl acetate (4g). Yield: 301 mg (73%), light yellow solid: mp 141–142 C; IR (KBr): 3413, 3303, 2984, 1742, 1628, 1489, 1446, 1210, 1046, 957, 830, 827, 763, 526 cm-1; 1H NMR (600 MHz, CDCl3): δ = 7.40–7.11 (m, 9H, PhH), 6.00 (br, 2H, NH2), 5.04 (s, 2H, PhCH2), 4.04–4.00 (m, 2H, OCH2), 3.56 (s, 2H, CH2),


15


1.19–1.16 (m, 3H, CH3);

Page 16 of 35

13

C{1H} NMR (150 MHz, CDCl3): δ = 169.7, 144.2, 134.0, 133.3,

131.7, 130.9, 129.4, 128.5, 128.1, 126.0, 119.0, 117.2, 116.8, 61.6, 46.6, 30.6, 14.0; HRMS (TOF ESI+): m/z calcd for C21H21O4N3Cl [M+H]+, 414.1215; found, 414.1213. 2-(5-Amino-3-(4-chlorophenyl)-1-(2,4-difluorobenzyl)-4-nitro-1H-pyrrol-2-yl) ethyl acetate (4h). Yield: 336 mg (75%), light yellow solid: mp 134–135.5 C; IR (KBr): 3401, 3303, 1742, 1625, 1488, 1396, 1227, 1139, 1092, 964, 834 cm-1; 1H NMR (600 MHz, CDCl3): δ = 7.35–6.88 (m, 7H, PhH), 6.11 (br, 2H, NH2), 5.03 (s, 2H, PhCH2), 4.05–4.02 (m, 2H, OCH2), 3.35 (s, 2H, CH2), 1.21–1.18 (m, 3H, CH3);

13

C{1H}NMR (150 MHz, CDCl3): δ = 169.6, 163.0 (d, 1JCF =

250.5 Hz), 160.2 (d, 1JCF = 247.5 Hz), 144.0, 133.5, 131.6, 130.7, 128.7, 128.1, 118.7, 117.5, 117.4, 116.8, 112.3(d, 2JCF = 18.0 Hz), 104.57, (t, 2JCF = 25.5 Hz, 2JCF = 24.0 Hz), 61.6, 40.4, 30.5, 14.0; 19F{1H} NMR (564 MHz, CDCl3): δ = -108.7 (d, J = 8.0 Hz), -113.0 (d, J = 7.9 Hz); HRMS (TOF ESI+): m/z calcd for C21H19O4N3F2Cl [M+H]+, 450.1027; found, 450.1024. 2-(5-Amino-3-(4-fluorophenyl)-1-(4-methoxyphenethyl)-4-nitro-1H-pyrrol-2-yl) ethyl acetate (4i). Yield: 382 mg (87%), light yellow solid: mp 123–124 C; IR (KBr): 3410, 3294, 2936, 1734, 1629, 1513, 1385, 1243, 1130, 1036, 831 cm-1; 1H NMR (600 MHz, CDCl3): δ = 7.26– 6.84 (m, 8H, PhH), 5.80 (br, 2H, NH2), 4.17–4.14 (m, 2H, OCH2), 3.94–3.92 (m, 2H, CH2), 3.78 (s, 3H, OCH3), 3.14 (s, 2H, CH2), 2.91–2.89 (m, 2H, CH2), 1.26–1.24 (m, 3H, CH3);

13

C{1H}

NMR (150 MHz, CDCl3): δ =170.1, 162.2 (d, 1JCF = 244.5 Hz), 159.1, 144.0, 131.9, 129.9, 129.2, 128.5, 118.8, 117.0, 116.9, 114.8 (d, 2JCF = 21.0 Hz), 114.6, 61.5, 55.3, 45.2, 34.2, 30.2, 14.1; HRMS (TOF ESI+): m/z calcd for C23H25O5N3F [M+H]+, 442.1773; found, 442.1773. 2-(5-Amino-1-(4-fluorophenethyl)-3-(4-methoxyphenyl)-4-nitro-1H-pyrrol-2-yl) ethyl acetate (4j). Yield: 365 mg (83%), light yellow solid: mp 148–149 C; IR (KBr): 3414, 3289, 1734, 1629, 1512, 1385, 1245, 1127, 1034, 832 cm-1; 1H NMR (500 MHz, CDCl3): δ = 7.26–6.88 (m,


16

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8H, PhH), 6.01(br, 2H, NH2), 4.17–4.13 (m, 2H, OCH2), 3.94–3.92 (m, 2H, CH2), 3.81 (s, 3H, OCH3), 3.13 (s, 2H, CH2), 2.95–2.92 (m, 2H, CH2), 1.26–1.23 (m, 3H, CH3);

13

C{1H} NMR

(125 MHz, CDCl3): δ =170.3, 162.1 (d, 1JCF = 245 Hz), 158.9, 144.0, 133.1, 131.3, 130.4, 124.7, 118.6, 117.7, 117.1, 116.0, (d, 2JCF = 21.3 Hz), 113.4, 61.5, 55.2, 44.8, 34.0, 30.3, 14.1; HRMS (TOF ESI+): m/z calcd for C23H25O5N3F [M+H]+, 442.1773; found, 442.1767. 2-(5-Amino-1-(4-methoxyphenethyl)-3-(4-methoxyphenyl)-4-nitro-1H-pyrrol-2-yl) ethyl acetate (4k). Yield: 370 mg (82%), light yellow solid: mp 120–120.5 C; IR (KBr): 3416, 3293, 1735, 1626, 1513, 1412, 1246, 1177, 1033, 832 cm-1; 1H NMR (500 MHz, CDCl3): δ = 7.19–6.83 (m, 8H, PhH), 5.79 (br, 2H, NH2), 4.18–4.13 (m, 2H, OCH2), 3.94–3.91 (m, 2H, CH2), 3.81 (s, 3H, OCH3), 3.78 (s, 3H, OCH3), 3.17 (s, 2H, CH2), 2.91–2.88 (m, 2H, CH2), 1.27–1.24 (m, 3H, CH3); 13

C{1H} NMR (125 MHz, CDCl3): δ = 170.3, 159.0, 158.8, 144.0, 131.4, 129.9, 129.3, 124.8,

118.6, 117.7, 117.1, 114.6, 113.3, 61.4, 55.3, 55.2, 45.2, 34.2, 30.3, 14.2; HRMS (TOF ESI+): m/z calcd for C24H28O6N3 [M+H]+, 454.1973; found, 454.1973. 2-(5-Amino-3-(4-fluorophenyl)-4-nitro-1-(3-phenylpropyl)-1H-pyrrol-2-yl) ethyl acetate (4l). Yield: 377 mg (89%), light yellow solid: mp 79–79.5 C; IR (KBr): 3394, 3290, 2936, 1735, 1625, 1492, 1413, 1223, 1129, 1029, 839, 698 cm-1; 1H NMR (600 MHz, CDCl3): δ = 7.31–7.00 (m, 9H, PhH), 6.21 (br, 2H, NH2), 4.13–4.09 (m, 2H, OCH2), 3.70–3.68 (m, 2H, CH2), 3.27 (s, 2H, CH2), 2.67–2.65 (m, 2H, CH2), 2.03–1.98 (m, 2H, CH2), 1.24–1.21 (m, 3H, CH3); 13C{1H} NMR (150 MHz, CDCl3): δ = 169.9, 162.2 (d, 1JCF = 246.0 Hz), 144.1, 140.1, 131.9, 128.8, 128.5, 128.3, 126.6, 118.7, 116.9, 116.7, 114.7 (d, 2JCF = 21.0 Hz), 61.5, 42.1, 32.6, 30.4, 29.8, 14.1; HRMS (TOF ESI+): m/z calcd for C23H25O4N3F [M+H]+, 426.1824; found, 426.1829. 2-(5-Amino-1-butyl-3-(4-chlorophenyl)-4-nitro-1H-pyrrol-2-yl) ethyl acetate (4m). Yield: 325 mg (86%), light yellow solid: mp 107.5–108 C; IR (KBr): 3432, 3318, 2967, 1733, 1632, 1485,


17


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1395, 1235, 1113, 1024, 832 cm-1; 1H NMR (600 MHz, CDCl3): δ = 7.33–7.22 (m, 4H, PhH), 6.25 (br, 2H, NH2), 4.18–4.15 (m, 2H, OCH2), 3.71–3.69 (m, 2H, CH2), 3.37 (s, 2H, CH2), 1.68– 1.62 (m, 2H, CH2), 1.39–1.35 (m, 2H, CH2), 1.28–1.25 (m, 3H, CH3), 0.97–0.95 (m, 3H, CH3); 13

C{1H} NMR (150 MHz, CDCl3): δ = 169.9, 143.9, 133.2, 131.6, 131.1, 128.0, 118.7, 116.8,

116.7, 61.6, 43.0, 30.8, 30.5, 20.1, 14.1, 13.6; HRMS (TOF ESI+): m/z calcd for C18H22O4N3ClNa [M+Na]+, 402.1191; found, 402.1190. General procedure for the synthesis of 1,2,3,4-tetrahydrobicyclic pyrroles 5. MBH acetate 1 (1.2 mmol), HKA derivative 3 (1.0 mmol) and dioxane ( 10 mL) were placed into a 25 mL round-bottom flask and the mixture was stirred at room temperature, then DBU (1.0 mmol) was added under stirring at room temperature, the mixture was stirred until the completion of the reaction was monitored by TLC (about 10 min). The reaction mixture was extracted with dichloromethane (3×10 mL), washed with water and brine, respectively, and dried over Na2SO4. The combined organic phases were evaporated under reduced pressure to afford the crude product. Finally, the product was obtained in pure form through column chromatography over silica gel using a mixture of petroleum ether/ethyl acetate (3:1, v/v) as the eluent. 2-(7-(4-Fluorophenyl)-8-nitro-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrimidin-6-yl) ethyl acetate (5a). Yield: 315 mg (91%), light yellow solid: mp 160–161 C; IR (KBr): 3341, 2973, 1727, 1627, 1508, 1417, 1223, 1150, 1020, 848, 760, 593 cm-1; 1H NMR (500 MHz, CDCl3): δ = 7.59 (br, 1H, NH), 7.27–7.02 (m, 4H, PhH), 4.20–4.16 (m, 2H, OCH2), 3.86–3.83 (m, 2H, NCH2), 3.57–3.54 (m, 2H, NCH2), 3.37 (s, 2H, CH2), 2.21–2.18 (m, 2H, CH2), 1.29–1.26 (m, 3H, CH3); 13

C{1H} NMR (125 MHz, CDCl3): δ = 170.0, 162.1 (d, 1JCF = 243.8 Hz), 143.6, 132.0, 128.2,

118.6, 116.2, 115.4, 114.7 (d, 2JCF = 21.3 Hz), 61.5, 40.5, 38.3, 30.1, 20.8, 14.2; HRMS (TOF ESI+): m/z calcd for C17H19O4N3F [M+H]+, 348.1354; found, 348.1354.


18

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2-(7-(4-Chlorophenyl)-8-nitro-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrimidin-6-yl) ethyl acetate (5b). Yield: 320 mg (88%), yellow solid: mp 201.5–202 C; IR (KBr): 3330, 2972, 1731, 1625, 1514, 1409, 1295, 1145, 1089, 1027, 834, 632 cm-1; 1H NMR (500 MHz, DMSO-d6): δ = 8.21 (br, 1H, NH), 7.40–7.17 (m, 4H, PhH), 4.12–4.08 (m, 2H, OCH2), 3.81–3.78 (m, 2H, NCH2), 3.45–3.43 (m, 2H, NCH2), 3.33 (s, 2H, CH2), 2.02–2.01 (m, 2H, CH2), 1.20–1.17 (m, 3H, CH3); 13

C{1H} NMR (125 MHz, DMSO-d6): δ = 170.1, 143.9, 132.3, 132.1, 131.9, 128.0, 120.3, 114.5,

114.2, 61.4, 40.7, 38.4, 30.1, 20.5, 14.5; HRMS (TOF ESI+): m/z calcd for C17H19N3O4Cl [M+H]+, 364.1059; found, 364.1060. 2-(8-Nitro-7-phenyl-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrimidin-6-yl) ethyl acetate (5c). Yield: 269 mg (82%), light yellow solid: mp 148–149 C; IR (KBr): 3344, 2976, 1726, 1624, 1510, 1413, 1186, 1090, 1049, 761, 702, 622 cm-1; 1H NMR (600 MHz, CDCl3): δ = 7.60 (br, 1H, NH), 7.37–7.26 (m, 5H, PhH), 4.20–4.16 (m, 2H, OCH2), 3.85–3.83 (m, 2H, NCH2), 3.56–3.54 (m, 2H, NCH2), 3.28 (s, 2H, CH2), 2.20–2.16 (m, 2H, CH2), 1.28–1.26 (m, 3H, CH3);

13

C{1H} NMR

(150 MHz, CDCl3): δ = 170.1, 143.6, 132.3, 130.3, 127.7, 127.1, 118.5, 117.3, 115.4, 61.4, 40.5, 38.3, 30.2, 20.8, 14.2; HRMS (TOF ESI+): m/z calcd for C17H20O4N3 [M+H]+, 330.1448; found, 330.1448. 2-(7-(4-Methoxyphenyl)-8-nitro-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrimidin-6-yl) ethyl acetate (5d). Yield: 280 mg (78%), light yellow solid: mp 206–207 C; IR (KBr): 3323, 2879, 1735, 1625, 1518, 1408, 1270, 1089, 1025, 835, 755, 632 cm-1; 1H NMR (600 MHz, CDCl3): δ = 7.58 (br, 1H, NH), 7.21–6.89 (m, 4H, PhH), 4.20–4.16 (m, 2H, OCH2), 3.84–3.83 (m, 2H, NCH2), 3.82 (s, 3H, OCH3), 3.56-3.54 (m, 2H, NCH2), 3.38 (s, 2H, CH2), 2.20–2.17 (m, 2H, CH2), 1.29– 1.26 (m, 3H, CH3);

13

C{1H} NMR (150 MHz, CDCl3): δ = 170.2, 158.8, 143.5, 131.4, 124.5,

118.3, 116.9, 115.5, 113.3, 61.4, 55.2, 40.4, 38.3, 30.2, 20.8, 14.2; HRMS (TOF ESI+): m/z calcd


19


Page 20 of 35

for C18H22O5N3 [M+H]+, 360.1554; found, 360.1548. 2-(7-(2-Bromophenyl)-8-nitro-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrimidin-6-yl) ethyl acetate (5e). Yield: 350 mg (86%), light yellow solid: mp 183 C; IR (KBr): 3365, 2974, 1732, 1637, 1514, 1421, 1211, 1185, 1096, 1018, 755, 543 cm-1; 1H NMR (500 MHz, DMSO-d6): δ = 8.13 (br, 1H, NH), 7.64–7.17 (m, 4H, PhH), 4.07–4.03 (m, 2H, OCH2), 3.92–3.76 (m, 2H, NCH2), 3.45 (s, 2H, CH2), 3.41–3.24 (m, 2H, NCH2), 2.04–2.03 (m, 2H, CH2), 1.16–1.13 (m, 3H, CH3); 13

C{1H} NMR (125 MHz, DMSO-d6): δ = 169.6, 143.3, 134.9, 132.4, 129.5, 127.6, 126.0, 119.8,

115.2, 114.6, 61.2, 40.7, 38.4, 29.9, 20.5, 14.4; HRMS (TOF ESI+): m/z calcd for C17H19N3O4Br [M+H]+, 408.0553; found, 408.0551. 2-(7-(2,4-Dichlorophenyl)-8-nitro-1,2,3,4-tetrahydropyrrolo[1,2-a]pyramidin-6-yl) ethyl aceta -te (5f). Yield: 353 mg (89%), light yellow solid: mp 170–171 C; IR (KBr): 3362, 2976, 2879, 1739, 1634, 1517, 1417, 1155, 1091, 1025, 826, 619 cm-1; 1H NMR (600 MHz, CDCl3): δ = 7.50 (br, 1H, NH), 7.45–7.16 (m, 3H, PhH), 4.16–4.12 (m, 2H, NCH2), 3.91–3.85 (m, 2H, NCH2), 3.59–3.56 (m, 2H, CH2), 3.33–3.24 (m, 2H, OCH2), 2.24–2.20 (m, 2H, CH2), 1.26–1.23 (m, 3H, CH3);

13

C{1H} NMR (150 MHz, CDCl3): δ = 169.4, 143.2, 136.1, 134.0, 132.9, 130.5, 129.1,

126.6, 118.8, 115.7, 113.1, 61.5, 40.6, 38.2, 30.1, 20.7, 14.1; HRMS (TOF ESI+): m/z calcd for C17H18N3O4Cl2 [M+H]+, 398.0669; found, 398.0670. 2-(8-(4-Chlorobenzoyl)-7-(4-fluorophenyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrimidin-6-yl) ethyl acetate (5g). Yield: 395 mg (90%), light yellow solid: mp 158–158.5 C; IR (KBr): 3328, 2967, 2842, 1725, 1613, 1536, 1264, 1070, 1031, 883, 769, 635 cm-1; 1H NMR (500 MHz, CDCl3): δ = 7.94 (br, 1H, NH), 7.09–6.66 (m, 8H, PhH), 4.21–4.17 (m, 2H, OCH2), 3.90–3.87 (m, 2H, NCH2), 3.54–3.51 (m, 2H, NCH2), 3.38 (s, 2H, CH2), 2.22–2.20 (m, 2H, CH2), 1.29– 1.27 (m, 3H, CH3); 13C{1H} NMR (125 MHz, CDCl3): δ = 188.2, 170.7, 161.4 (d, 1JCF = 243.8


20

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Hz), 148.6, 139.3, 135.0, 131.7, 130.8, 129.5, 127.0, 120.3, 117.0, 114.3 (d, 2JCF = 21.3 Hz), 102.2, 61.2, 40.4, 38.1, 30.5, 21.3, 14.2; HRMS (TOF ESI+): m/z calcd for C24H23O3N2ClF [M+H]+, 441.1376; found, 441.1370. 2-(8-Benzoyl-7-(4-fluorophenyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrimidin-6-yl) ethyl acetate (5h). Yield: 344 mg (85%), light yellow solid: mp 161.5–162 C; IR (KBr): 3317, 2972, 1725, 1616, 1472, 1327, 1233, 1113, 1025, 835, 705, 636 cm-1; 1H NMR (500 MHz, CDCl3): δ = 7.97 (br, 1H, NH), 7.14–6.60 (m, 9H, PhH), 4.21–4.16 (m, 2H, OCH2), 3.90–3.87 (m, 2H, NCH2), 3.53–3.51 (m, 2H, NCH2), 3.39 (s, 2H, CH2), 2.23–2.19 (m, 2H, CH2), 1.29–1.26 (m, 3H, CH3); 13

C{1H} NMR (125 MHz, CDCl3): δ = 189.9, 170.8, 162.2 (d, 1JCF = 243.8 Hz), 148.4, 140.9,

131.7, 131.0, 128.9, 128.0, 126.9, 120.6, 116.7, 114.1(d, 2JCF = 21.3 Hz), 102.2, 61.2, 40.4, 38.1, 30.5, 21.4, 14.2; HRMS (TOF ESI+): m/z calcd for C24H24O3N2F [M+H]+, 407.1765; found, 407.1765. 2-(7-(4-Fluorophenyl)-8-(4-methoxybenzoyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrimidin-6-yl) ethyl acetate (5i). Yield: 330 mg (76%), light yellow solid: mp 173–174.5 C; IR (KBr): 3431, 3335, 2966, 1722, 1607, 1507, 1440, 1253, 1164, 1030, 835, 777 cm-1; 1H NMR (600 MHz, CDCl3): δ = 7.87 (br, 1H, NH), 7.27–6.43 (m, 8H, PhH), 4.21–4.18 (m, 2H, OCH2), 3.90–3.88 (m, 2H, NCH2), 3.68 (s, 3H, OCH3) 3.52–3.50 (m, 2H, NCH2), 3.41 (s, 2H, CH2), 2.23–2.19 (m, 2H, CH2), 1.30–1.27 (m, 3H, CH3); 13C{1H} NMR (150 MHz, CDCl3): δ = 189.2, 170.8, 161.2 (d, 1JCF = 243.0 Hz), 160.5, 148.2, 133.5, 131.7, 131.3, 130.0, 120.6, 116.5, 114.2 (d, 2JCF = 21.0 Hz), 112.3, 102.0, 61.2, 55.2, 40.5, 38.1, 30.6, 21.5, 14.2; HRMS (TOF ESI+): m/z calcd for C25H26O4N2F [M+H]+, 437.1871; found, 437.1869. 2-(7-(4-Chlorophenyl)-8-(4-fluorobenzoyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrimidin-6-yl) ethyl acetate (5j). Yield: 391 mg (89%), light yellow solid: mp 170.5–172 C; IR (KBr): 339,


21


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2966, 1725, 1618, 1417, 1226, 1184, 910, 842, 773, 641 cm-1; 1H NMR (600 MHz, CDCl3): δ = 7.92 (br, 1H, NH), 7.16–6.61 (m, 8H, PhH), 4.21–4.18 (m, 2H, OCH2), 3.90–3.88 (m, 2H, NCH2), 3.53–3.51 (m, 2H, NCH2), 3.39 (s, 2H, CH2), 2.23–2.19 (m, 2H, CH2), 1.30–1.27 (m, 3H, CH3);

13

C{1H} NMR (150 MHz, CDCl3): δ = 188.3, 170.7, 163.2 (d, 1JCF = 247.5 Hz), 148.5,

137.0, 133.5, 131.8, 131.5, 130.3, 127.6, 120.2, 117.0, 113.8 (d, 2JCF = 22.5 Hz), 101.9, 61.3, 40.5, 38.0, 30.5, 21.4, 14.2; HRMS (TOF ESI+): m/z calcd for C24H23O3N2ClF [M+H]+, 441.1376; found, 441.1378. 2-(8-(4-Chlorobenzoyl)-7-(4-chlorophenyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrimidin-6-yl) ethyl acetate (5k). Yield: 396 mg (87%), yellow solid: mp 174.5–175.5 C; IR (KBr): 3348, 2966, 1737, 1606, 1529, 1418, 1263, 1176, 1085, 1023, 840, 770, 628 cm-1; 1H NMR (600 MHz, CDCl3): δ = 7.94 (br, 1H, NH), 7.08–6.76 (m, 8H, PhH), 4.21–4.17 (m, 2H, OCH2), 3.89–3.88 (m, 2H, NCH2), 3.54–3.51 (m, 2H, NCH2), 3.39 (s, 2H, CH2), 2.23–2.20 (m, 2H, CH2), 1.30– 1.27 (m, 3H, CH3);

13

C{1H} NMR (150 MHz, CDCl3): δ = 188.2, 170.6, 148.6, 139.2, 135.1,

133.4, 132.0, 131.5, 129.4, 127.6, 127.1, 120.2, 117.1, 102.0, 61.3, 40.5, 38.1, 30.5, 21.3, 14.2; HRMS (TOF ESI+): m/z calcd for C24H23O3N2Cl2 [M+H]+, 457.1080; found, 457.1075. 2-(8-Benzoyl-7-(4-chlorophenyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrimidin-6-yl)ethyl acetate (5l). Yield: 354 mg (84%), light yellow solid: mp 167.5–168 C; IR (KBr): 3342, 2963, 1724, 1613, 1537, 1414, 1185, 1102, 831, 741, 704, 635 cm-1; 1H NMR (600 MHz, CDCl3): δ = 7.97 (br, 1H, NH), 7.14–6.76 (m, 9H, PhH), 4.21–4.17 (m, 2H, OCH2), 3.90–3.88 (m, 2H, NCH2), 3.53–3.51 (m, 2H, NCH2), 3.39 (s, 2H, CH2), 2.23–2.19 (m, 2H, CH2), 1.29–1.27 (m, 3H, CH3); 13

C{1H} NMR (150 MHz, CDCl3): δ = 189.8, 170.7, 148.5, 140.8, 133.6, 131.5, 131.4, 129.0,

128.0, 127.4, 126.9, 120.5, 116.8, 102.0, 61.2, 40.5, 38.1, 30.5, 21.4, 14.2; HRMS (TOF ESI+): m/z calcd for C24H24O3N2Cl [M+H]+, 423.1470; found, 423.1469.


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2-(7-(4-Chlorophenyl)-8-(4-methylbenzoyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrimidin-6-yl) ethyl acetate (5m). Yield: 352 mg (81%), light yellow solid: mp 172–174 C; IR (KBr): 3340, 2969, 1720, 1608, 1527, 1375, 1167, 1088, 911, 832, 770 cm-1; 1H NMR (600 MHz, CDCl3): δ = 7.91 (br, 1H, NH), 7.02–6.71 (m, 8H, PhH), 4.21–4.16 (m, 2H, OCH2), 3.89–3.87 (m, 2H, NCH2), 3.52–3.51 (m, 2H, NCH2), 3.39 (s, 2H, CH2), 2.22–2.19 (m, 2H, CH2), 2.21(s, 3H, CH3) 1.29–1.26 (m, 3H, CH3); 13C{1H} NMR (150 MHz, CDCl3): δ = 190, 170.7, 148.3, 139.2, 138.0, 133.7, 131.5, 128.1, 127.5, 127.3, 120.6, 116.6, 102.1. 61.2, 40.5, 38.1, 30.5, 21.4, 21.2, 14.2; HRMS (TOF ESI+): m/z calcd for C25H26O3N2Cl [M+H]+, 437.1626; found, 437.1622. 2-(7-(4-Chlorophenyl)-8-(4-methoxybenzoyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrimidin-6-yl) ethyl acetate (5n). Yield: 353 mg (78%), Light yellow solid: mp 156–156.5 C; IR (KBr): 3327, 2964, 1723, 1606, 1530, 1418, 1251, 1191, 1027, 834, 777, 539 cm-1; 1H NMR (500 MHz, CDCl3): δ = 7.88 (br, 1H, NH), 7.12–6.42 (m, 8H, PhH), 4.22–4.17 (m, 2H, OCH2), 3.88–3.87 (m, 2H, NCH2), 3.69 (s, 3H, OCH3), 3.52–3.50 (m, 2H, NCH2), 3.41 (s, 2H, CH2), 2.23–2.18 (m, 2H, CH2), 1.30–1.27 (m, 3H, CH3); 13C{1H} NMR (125 MHz, CDCl3): δ = 189.1, 170.8, 160.6, 148.2, 133.9, 133.4, 131.5, 131.4, 130.0, 127.4, 120.5, 116.5, 112.3, 101.9, 61.2, 55.3, 40.5, 38.1, 30.6, 21.5, 14.2; HRMS (TOF ESI+): m/z calcd for C25H26O4N2Cl [M+H]+, 453.1576; found, 453.1572. 2-(8-(2-Chlorobenzoyl)-7-(4-chlorophenyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrimidin-6-yl) ethyl acetate (5o). Yield: 392 mg (86%), light yellow solid: mp 175.5–176.5 C; IR (KBr): 3305, 2963, 1728, 1617, 1541, 1397, 1258, 1184, 1115, 1042, 831, 777, 646 cm-1; 1H NMR (500 MHz, CDCl3): δ =8.05 (br, 1H, NH), 7.00–6.78 (m, 8H, PhH), 4.16–4.12 (m, 2H, OCH2), 3.88–3.85 (m, 2H, NCH2), 3.54 (m, 2H, NCH2), 3.30 (s, 2H, CH2), 2.24–2.19 (m, 2H, CH2), 1.26–1.23 (m, 3H, CH3);

13

C{1H} NMR (125 MHz, CDCl3): δ = 186.6, 170.5, 148.6, 140.5, 132.5, 131.8, 131.5,


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130.5, 129.0, 128.9, 128.8, 127.1, 125.7, 120.2, 117.3, 102.9, 61.2, 40.3, 38.0, 30.3, 21.2, 14.2; HRMS (TOF ESI+): m/z calcd for C24H23O3N2Cl2 [M+H]+, 457.1080; found, 457.1080. 2-(8-(4-Fluorobenzoyl)-7-phenyl-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrimidin-6-yl) ethyl acetate (5p). Yield: 336 mg (83%), light yellow solid: mp 148–148.5 C; IR (KBr): 3320, 2277, 1727, 1617, 1540, 1418, 1294, 1183, 1114, 851, 776, 603 cm-1; 1H NMR (600 MHz, CDCl3): δ = 7.93 (br, 1H, NH), 7.17–6.54 (m, 9H, PhH), 4.21–4.18 (m, 2H, OCH2), 3.90–3.88 (m, 2H, NCH2), 3.54–3.51 (m, 2H, NCH2), 3.43 (s, 2H, CH2), 2.24–2.20 (m, 2H, CH2), 1.30–1.27 (m, 3H, CH3); 13

C{1H} NMR (150 MHz, CDCl3): δ = 188.4, 170.9, 163.1 (d, 1JCF = 247.5 Hz), 148.5, 137.1,

134.9, 130.3, 130.2, 127.4, 125.8, 121.5, 116.8, 113.7 (d, 2JCF = 21.0 Hz), 102.0, 61.2, 40.4, 38.1, 30.6, 21.4, 14.2; HRMS (TOF ESI+): m/z calcd for C24H24O3N2F [M+H]+, 407.1765; found, 407.1761. 2-(8-Benzoyl-7-phenyl-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrimidin-6-yl)ethyl

acetate

(5q).

Yield: 302 mg (78%), light yellow solid: mp 163.5–164 C; IR (KBr): 3319, 2972, 1725, 1612, 1537, 1412, 1275, 1185, 1114, 1028, 905, 767, 704 cm-1; 1H NMR (500 MHz, CDCl3): δ = 7.98 (br, 1H, NH), 7.17–6.84 (m, 10H, PhH), 4.21–4.17 (m, 2H, OCH2), 3.90–3.88 (m, 2H, NCH2), 3.52 (m, 2H, NCH2), 3.42 (s, 2H, CH2), 2.22–2.20 (m, 2H, CH2), 1.29–1.27 (m, 3H, CH3); 13

C{1H} NMR (125 MHz, CDCl3): δ = 189.9, 171.0, 148.5, 140.9, 135.0, 130.3, 128.8, 128.1,

127.3, 126.8, 125.5, 121.7, 116.7, 102.1, 61.1, 40.4, 38.1, 30.6, 21.5, 14.2; HRMS (TOF ESI+): m/z calcd for C24H25O3N2 [M+H]+, 389.1860; found, 389.1859. 2-(8-(4-Methylbenzoyl)-7-phenyl-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrimidin-6-yl) ethyl acetate (5r). Yield: 296 mg (74%), light yellow solid: mp 124.5–125 C; IR (KBr): 3340, 2865, 1741, 1611, 1530, 1418, 1175, 766, 709, 604 cm-1; 1H NMR (500 MHz, CDCl3): δ = 7.94 (br, 1H, NH), 7.06–6.65 (m, 9H, PhH), 4.21–4.17 (m, 2H, OCH2), 3.89–3.87 (m, 2H, NCH2), 3.52–3.50 (m, 2H,


24

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NCH2), 3.43 (s, 2H, CH2), 2.21–2.19 (m, 2H, CH2), 2.14 (s, 3H, CH3), 1.29–1.26 (m, 3H, CH3); 13

C{1H} NMR (125 MHz, CDCl3): δ = 190.0, 171.0, 148.3, 138.8, 138.1, 135.2, 130.3, 128.2,

127.4, 127.2, 125.3, 121.8, 116.5, 102.1, 61.1, 40.4, 38.1, 30.6, 21.5, 21.2, 14.2; HRMS (TOF ESI+): m/z calcd for C25H27O3N2 [M+H]+, 403.2016; found, 403.2018. 2-(7-(2-Bromophenyl)-8-(4-fluorobenzoyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrimidin-6-yl) ethyl acetate (5s). Yield: 420 mg (87%), light yellow solid: mp 153.5–154 C; IR (KBr): 3362, 2974, 1737, 1612, 1541, 1474, 1273, 1178, 1023, 853, 775, 602 cm-1; 1H NMR (500 MHz, CDCl3): δ = 7.91 (br, 1H, NH), 7.28–6.55 (m, 8H, PhH), 4.13–4.08 (m, 2H, NCH2), 3.97–3.84 (m, 2H, NCH2), 3.54 (s, 2H, CH2), 3.36–3.27 (m, 2H, OCH2), 2.24–2.21 (m, 2H, CH2), 1.23– 1.20 (m, 3H, CH3); 13C{1H} NMR (125 MHz, CDCl3): δ = 188.6, 170.3, 162.9 (d, 1JCF = 246.3 Hz), 148.3, 137.1, 136.1, 133.3, 132.2, 129.8, 128.0, 126.5, 125.4, 119.7, 117.5, 113.4 (d, 2JCF = 21.3 Hz), 102.1, 61.1, 40.5, 38.1, 30.6, 21.3, 14.2; HRMS (TOF ESI+): m/z calcd for C24H23O3N2BrF [M+H]+, 485.0871; found, 485.0867. 2-(7-(2-Bromophenyl)-8-(4-chlorobenzoyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrimidin-6-yl) ethyl acetate (5t). Yield: 420 mg (84%), Light yellow solid: mp 143–143.5 C; IR (KBr): 3358, 2975, 1738, 1612, 1535, 1421, 1177, 1083, 853, 771 cm-1; 1H NMR (600 MHz, CDCl3): δ = 7.93 (br, 1H, NH), 7.27–6.84 (m, 8H, PhH), 4.14–4.07 (m, 2H, NCH2), 3.96–3.84 (m, 2H, NCH2), 3.56–3.52 (m, 2H, CH2), 3.35–2.27 (m, 2H, OCH2), 2.25–2.19 (m, 2H, CH2), 1.23–1.20 (m, 3H, CH3);

13

C{1H} NMR (150 MHz, CDCl3): δ = 188.5, 170.2, 148.4, 139.3, 136.0, 134.5, 133.3,

132.2, 129.0, 128.0, 126.7, 126.5, 125.4, 119.6, 117.5, 102.2, 61.1, 40.5, 38.1, 30.6, 21.3, 14.2; HRMS (TOF ESI+): m/z calcd for C24H23O3N2BrCl [M+H]+, 501.0575; found, 501.0569. 2-(8-Benzoyl-7-(2-bromophenyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrimidin-6-yl) ethyl acetate (5u). Yield: 377 mg (81%), light yellow solid: mp 125.5–126 C; IR (KBr): 3333, 2972, 1724,


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1610, 1537, 1410, 1273, 1184, 1022, 905, 754, 701 cm-1; 1H NMR (600 MHz, CDCl3): δ = 7.96 (br, 1H, NH), 7.24–6.81 (m, 9H, PhH), 4.13–4.08 (m, 2H, NCH2), 3.95–3.85 (m, 2H, NCH2), 3.55–3.53 (m, 2H, CH2), 3.34–2.27 (m, 2H, OCH2), 2.24–2.21 (m, 2H, CH2), 1.22–1.19 (m, 3H, CH3);

13

C{1H} NMR (150 MHz, CDCl3): δ = 190.1, 170.3, 148.3, 140.9, 136.2, 133.3, 132.1,

128.6, 127.8, 127.6, 126.6, 126.3, 125.4, 119.9, 117.3, 102.1, 61.0, 40.5, 38.1, 30.6, 21.4, 14.2; HRMS (TOF ESI+): m/z calcd for C24H24O3N2Br [M+H]+, 467.0965; found, 467.0971. 2-(7-(2,4-Dichlorophenyl)-8-(4-fluorobenzoyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrimidin-6-yl) ethyl acetate (5v). Yield: 426 mg (90%), light yellow solid: mp 157.5–158.5 C; IR (KBr): 3342, 2979, 1734, 1617, 1540, 1416, 1274, 1224, 1114, 1024, 840, 772, 603 cm-1; 1H NMR (600 MHz, CDCl3): δ = 7.88 (br, 1H, NH), 7.17–6.62 (m, 7H, PhH), 4.16–4.08 (m, 2H, NCH2), 3.96–3.84 (m, 2H, NCH2), 3.55–3.53 (m, 2H, CH2), 3.33–3.26 (m, 2H, OCH2), 2.27–2.18 (m, 2H, CH2), 1.24–1.21 (m, 3H, CH3); 13C{1H} NMR (150 MHz, CDCl3): δ = 188.5, 170.1, 163.1 (d, 1JCF = 247.5 Hz), 148.4, 137.0, 135.0, 133.8, 133.0, 129.8, 129.7, 128.7, 126.2, 117.8, 116.7, 113.6 (d, 2

JCF = 22.5 Hz), 102.0, 61.2, 40.5, 38.1, 30.5, 21.3, 14.2; HRMS (TOF ESI+): m/z calcd for

C24H22O3N2Cl2F [M+H]+, 475.0986; found, 475.0988. 2-(8-(4-Chlorobenzoyl)-7-(2,4-dichlorophenyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrimidin-6-yl) ethyl acetate (5w). Yield: 437 mg (89%), light yellow solid: mp 175.5–176 C; IR (KBr): 3370, 2983, 1736, 1610, 1534, 1476, 1270, 1181, 1084, 949, 837, 772, 633, 565 cm-1; 1H NMR (500 MHz, CDCl3): δ = 7.90 (br, 1H, NH), 7.11–6.80 (m, 7H, PhH), 4.15–4.09 (m, 2H, NCH2), 3.95– 3.84 (m, 2H, NCH2), 3.55–3.53 (m, 2H, CH2), 3.34–3.25 (m, 2H, OCH2), 2.26–2.19 (m, 2H, CH2), 1.24–1.21 (m, 3H, CH3);

13

C{1H} NMR (125 MHz, CDCl3): δ = 188.4, 170.1, 148.5,

139.2, 135.1, 135.0, 133.8, 133.3, 132.8, 129.0, 128.8, 126.9, 126.3, 117.9, 116.7, 102.1, 61.2, 40.5, 38.1, 30.5, 21.3, 14.2; HRMS (TOF ESI+): m/z calcd for C24H22N2O3Cl3 [M+H]+, 491.0691;


26

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found, 491.0693. 2-(8-Benzoyl-7-(2,4-dichlorophenyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrimidin-6-yl)

ethyl

Acetate (5x). Yield: 388 mg (85%), yellow solid: mp 144.5–145 C; IR (KBr): 3342, 2978, 1731, 1612, 1537, 1475, 1414, 1274, 1183, 1114, 1024, 905, 743, 703, 569 cm-1; 1H NMR (600 MHz, CDCl3): δ = 7.93 (br, 1H, NH), 7.15–6.79 (m, 8H, PhH), 4.15–4.07 (m, 2H, NCH2), 3.96–3.84 (m, 2H, NCH2), 3.54–3.52 (m, 2H, CH2), 3.33–3.25 (m, 2H, OCH2), 2.26–2.18 (m, 2H, CH2), 1.23–1.21 (m, 3H, CH3);

13

C{1H} NMR (150 MHz, CDCl3): δ = 190.0, 170.2, 148.3, 140.9,

135.0, 133.8, 132.9, 132.8, 128.7, 128.6, 127.5, 126.8, 126.1, 117.5, 116.9, 102.1, 61.1, 40.5, 38.1, 30.5, 21.3, 14.1; HRMS (TOF ESI+): m/z calcd for C24H23N2O3Cl2 [M+H]+, 457.1080; found, 457.1082. 2-(7-(2,4-Dichlorophenyl)-8-(4-methoxybenzoyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrimidin-6yl) ethyl acetate (5y). Yield: 375 mg (77%), light yellow solid: mp 151.5–152 C; IR (KBr): 3334, 2977, 1732, 1605, 1582, 1422, 1251, 1164, 1032, 859, 775, 608 cm-1; 1H NMR (600 MHz, CDCl3): δ = 7.85 (br, 1H, NH), 7.13–6.45 (m, 7H, PhH), 4.15–4.09 (m, 2H, NCH2), 3.95–3.84 (m, 2H, NCH2), 3.70 (s, 2H, OCH3), 3.54-3.51 (m, 2H, CH2), 3.35–3.28 (m, 2H, OCH2), 2.25– 2.18 (m, 2H, CH2), 1.24–1.21 (m, 3H, CH3); 13C{1H} NMR (150 MHz, CDCl3): δ = 189.4, 170.2, 160.4, 148.1, 135.1, 134.0, 133.5, 133.3, 132.6, 129.4, 128.7, 126.1, 117.3, 117.0, 112.1, 102.0, 61.1, 55.3, 40.5, 38.1, 30.6, 21.4, 14.2 ; HRMS (TOF ESI+): m/z calcd for C25H25O4N2Cl2 [M+H]+, 487.1186; found, 487.1181.



ASSOCIATED CONTENT

Supporting Information Spectroscopic and analytical data as well as the original copy of 1H and 13C NMR spectra of all


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new compounds and X-ray crystallographicdata (CIF file) of compound 4a and 5c (CCDC1868313 ＆ CCDC1868314). This material is available free of charge via the Internet at http://pubs.acs.org. 

AUTHOR INFORMATION

Corresponding Authors *E-mail: [email protected] (J. L) *E-mail: [email protected] (S.-J. Y). Tel/Fax: +86 87165031633. ORCID Jin Liu: 0000-0002-1488-2556 Jun Lin: 0000-0002-2087-6013. Sheng-Jiao Yan: 0000-0002-7430-4096 Notes The authors declare no competing financial interest. 

ACKNOWLEDGMENTS This work was supported by the Program for Changjiang Scholars and Innovative Research

Team in University (IRT17R94), the National Natural Science Foundation of China (Nos. 21662042, 81760621, 21362042, U1202221), the Natural Science Foundation of Yunnan Province (2017FA003), the High-Level Talents Introduction Plan of Yunnan Province, Donglu Schloars of Yunnan University, Excellent Young Talents of Yunnan University (XT412003), the Fund of National Demonstration Center for Experimental Chemistry and Chemical Engineering Education (Yunnan University) and Donglu Young Teacher Training Program of Yunnan University (WX069051). We also thank Dr. Rong Huang of Advanced Analysis and Measurement Center of Yunnan University for helpful testing the NMR.


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

REFERENCES (1) For selected reviews, see: (a) Gholap, S. S. Pyrrle: an emerging scaffold for construction of

valuable therapeutic agents. Eur. J. Med. Chem. 2016, 110, 13–31. (b) Bhardwaj, V.; Gumber, D.; Abbot, V.; Dhiman, S.; Sharma, P. Pyrrole: a resourceful small molecule in key medicinal hetero-aromatics. RSC Adv. 2015, 5, 15233–15266. (c) Yang, I. S.; Thornton, P. D.; Thompson, A. Synthesis of natural products containing the pyrrolic ring. Nat. Prod. Rep. 2010, 27, 1801– 1839. (d) Fan, H.; Peng, J.; Hamann, M. T.; Hu, J.-F. Lamellarins and related pyrrole-derived alkaloids from marine organisms. Chem. Rev. 2008, 108, 264–287. (e) De Coen, L. M.; Heugebaert, T. S. A.; Carcia, D.; Stevens, C. V. Synthetic entries to and biological activity of pyrrolopyrimidines. Chem. Rev. 2016, 116, 80–139. For selected examples, see (f) Laszlo, S. E.; Hacker, C.; Li, B.; Kim, D.; MacCoss, M.; Mantlo, N.; Pivnichny, J. V.; Colwell, L.; Koch, G. E.; Cascieri, M. A.; Hagmann, W. K. Potent, orally absorbed glucagon receptor antagonists. Bioorg. Med. Chem. Lett. 1999, 9, 641–646. (g) Chang, L. L.; Sidler, K. L.; Cascieri, M. A.; Laszol S.; Koch, G.; Li, B.; MacCoss, M.; Mantlo, N.; O’Keefe, S.; Pang, M.; Rolando, A.; Hagmann, W. K. Substituted imidazoles as glucagon receptor antagonists. Bioorg. Med. Chem. Lett. 2001, 11, 2549–2553. (h) Goel, A.; Agawal, N.; Singh, F. V.; Sharon, A.; Tiwari, P.; Manish, D.; Pratap, R.; Srivastava, A.; Maulik, P. R.; Ram, V. J. Bioorg. Med. Chem. Lett. 2004, 14, 1089–1092. (2) Wallace, M. B.; Adams, M. E.; Kanouni, T.; Mol, C. D.; Dougan, D. R.; Feher, V. A.; O’Connell, S. M.; Shi, L.; Halkowycz, P.; Dong, Q. Structure-based design and synthesis of pyrrole derivatives as MEK inhibitors. Bioorg. Med. Chem. Lett. 2010, 20, 4156–4158. (3) McGeary, R. P.; Tan, D. T. C.; Selleck, C.; Pedroso, M. M.; Sidjabat, H. E.; Schenk, G. Structure-activity relationship study and optimisation of 2-aminopyrrole-1-benzyl-4,5-diphenyl1H-pyrrole-3-carbonitrile as a broad spectrum metallo-β-lactamase inhibitor. Eur. J. Med. Chem.


29


Page 30 of 35

2017, 137, 351–364. (4) Wang, D.; Kosh, J. W.; Sowell, J. W., Sr.; Wang, T. Treatment or prevention of cardiovascular

and

respiratory

disorders

with

novel

substituted

cyclic

ampspecific

phosphodiesterase inhibitors. PCT Int. Appl. WO 2005046676 A1, 2005. (5) Bullington, J. L.; Fan, X.; Jackson, P. F.; Zhang, Y.-M. 3,4-Disubstituted pyrroles and their for use in treating inflammatory diseases. PCT Int. Appl. WO 2004029040 A1, 2004. (6) (a) Kourany-Lefoll, E.; Pais, M.; Sevenet, T.; Guittet, E.; Montagnac, A.; Fontaine, C.; Guenard, D.; Adeline, M. T.; Debitus, C. Phloeodictines A and B: new antibacterial and cytotoxic bicyclic amidinium salts from the new Caledonian sponge, Phloeodictyon sp. J. Org. Chem. 1992, 57, 3832–3835. (b) Kourany-Lefoll, E.; Laprevote, O.; Sevenet, T.; Montagnac, A.; Pais, M.; Debitus, C. Phloeodictines A1-A7 and C1-C2, antibiotic and cytotoxic guanidine alkaloids from the new Caledonian sponge, Phloeodictyon sp. Tetrahedron 1994, 50, 3415–3426. (c) Mancini, I.; Guella, G.; Sauvain, M.; Debitus, C.; Duigou, A. G.; Ausseil, F.; Menou, J. L.; Pietra, F. New 1,2,3,4-tetrahydropyrrolo-[1,2-a]pyrimidinium alkaloids (phloeodictynes) from the new Caledonian shallow-water haplosclerid sponge Oceanapia fistulosa. Structural elucidation from mainly LC-tandem-MS-soft-ionization techniques and discovery of antiplasmodial activity. Org. Biomol. Chem. 2004, 2, 783–787. (7) Vangrevelinghe, E.; Zimmermann, K.; Schoepfer, J.; Portmann, R.; Fabbro, D.; Furet, P. Discovery of a potent and selective protein kinase CK2 inhibitor by high-throughput docking. J. Med. Chem. 2003, 46, 2565–2662. (8) Nakazato, A.; Okubo, T.; Nozawa, D.; Tamita, T.; Kennis, L. E. J. Pyrrolopyrimidine and pyrrolotriazine derivatives. US 8106194 B2. 2012. (9) (a) Estevez, V.; Villacampa, M.; Menendez, J. C. Recent advances in the synthesis of


30

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pyrroles by multicomponent reactions. Chem. Soc. Rev. 2014, 43, 4633–4657. (b) Wang, X.; Xu, X.-P.; Wang, S.-Y.; Zhou, W.; Ji, S.-J. Highly efficient chemoselective synthesis of polysubstituted pyrroles via isocyanide-based multicomponent domino reaction. Org. Lett. 2013, 15, 4246−4249. (c) Estevez, V.; Villacampa, M.; Menendez, J. C. Multicomponent reactions for the synthesis of pyrroles. Chem. Soc. Rev. 2010, 39, 4402–4421. (d) Nair, V.; Viond, A. U.; Rajesh, C. A novel synthesis of 2-aminopyrroles using a three-component reaction. J. Org. Chem. 2001, 66, 4427–4429. (10) (a) Gulevich, A. V.; Dudnik, A. S.; Chernyak, N. Gevorgyan, V. Transition metalmediated synthesis of monocyclic aromatic heterocycles. Chem. Rev. 2013, 113, 3084–3213. (b) Ackermann, L. Carboxylate-assisted ruthenium-catalyzed alkyne annulations by C–H/Het–H bond functionalizations. Acc. Chem. Res. 2014, 47, 281–295.(c) Wu, Y.; Zhu, L.; Yu, Y.; Lou, X.; Huang X. Polysubstituted 2-aminopyrrole synthesis via gold-catalyzed intermolecular nitrene transfer from vinyl azide to ynamide: reaction scope and mechanistic insights. J. Org. Chem. 2015, 80, 11407–11416. (d) Li, L.; Tan, T.-D.; Zhang, Y.-Q.; Liu, X.; Ye, L.-W. Recent advances in transition-metal-catalyzed reactions of alkynes with isoxazoles. Org. Biomol. Chem. 2017, 15, 8483–8492. (11) (a) Knorr, L. Synthese von pyrrolderivaten. Ber. Dtsch. Chem. Ges. 1884, 17, 1635–1642. (b) Paal, C. Formation of pyrroles via cyclization of 1,4-dicarbonyl compounds with ammonia or primary amines. Biomed. Engineer. Res. 1885, 18, 367–371. (c) Hantzsch, A. Formation of pyrrole derivatives from α-chloromethyl ketones, β-keto esters and ammonia or amines. Biomed. Engineer. Res. 1890, 23, 1474–1476. (12) Shu, C.; Wang, Y.-H.; Shen, C.-H.; Ruan, P.-P.; Lu, X.; Ye, L.-W. Gold-catalyzed intermolecular ynamide amination-initiated aza-Nazarov cyclization: access to functionalized 2-


31


Page 32 of 35

aminopyrroles. Org. Lett. 2016, 18, 3254−3257. (13) Fontaine, P.; Masson, G.; Zhu, J. Synthesis of pyrroles by consecutive multicomponent reaction/[4+1] cycloaddition of α-iminonitriles with isocyanides. Org. Lett. 2009, 11, 1555−1558. (14) (a) Wang, K.-M.; Yan S.-J.; Lin, J. Heterocyclic ketene aminals: scaffolds for heterocycle molecular diversity. Eur. J. Org. Chem. 2014, 1129–1145. (b) Huang Z.-T.; Wang, M.-X. Heterocyclic ketene aminals. Heterocycles 1994, 37, 1233–1262. (15) (a) Huang, C.; Yan, S.-J.; Zeng, X.-H.; Dai, X.-Y.; Zhang, Y.; Qing, C.; Lin, J. Biological evaluation of polyhalo 1,3-diazaheterocycle fused isoquinolin-1(2H)-imine derivatives. Eur. J. Med. Chem. 2011, 46, 1172–1180. (b) Yan, S.-J.; Liu, Y.-J.; Chen, Y.-L.; Liu, L.; Lin, J. An efficient one-pot synthesis of heterocycle-fused 1,2,3-triazole derivatives as anti-cancer agents. Bioorg. Med. Chem. Lett. 2010, 20, 5225−5228. (c) Yu, F.-C.; Lin, X.-R.; Liu, Z.C.; Zhang, J.H.; Liu, F.-F.; Wu, W.; Ma, Y.-L.; Qu, W.-W.; Yan, S.-J.; Lin, J. Beyond the antagonism: selflabeled xanthone inhibitors as modeled “two-in-one” drugs in cancer therapy. ACS Omega 2017, 2, 873−889. (16) (a) Lu, S.; Shao, X.; Li, Z.; Xu, Z.; Zhao, S.; Wu, Y.; Xu, X. Design, synthesis, and particular biological behaviors of chain-opening nitromethylene neonicotinoids with cis configuration. J. Agric. Food Chem. 2012, 60, 322−330. (b) Chen, N.; Meng, X.; Zhu, F.; Cheng, J.; Shao, X.; Li, Z. Tetrahydroindeno[1’,2’:4,5]pyrrolo[1,2-a]imidazol-5(1H)-ones as novel neonicotinoid insecticides: reaction selectivity and substituent effects on the activity level. J. Agric. Food Chem. 2015, 63, 1360−1369. (c) Bao, H.; Shao, X.; Zhang, Y.; Deng, Y.; Xu, X.; Liu, Z.; Li, Z. Specific synergist for neonicotinoid insecticides: IPPA08, a cis-neonicotinoid compound with a unique oxabridged substructure. J. Agric. Food Chem. 2016, 64, 5148−5155. (17) Kondo, H.; Taguchi, M.; Inoue, Y.; Sakamoto, F.; Tsukamoto, G. Synthesis and


32

Page 33 of 35 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 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


antibacterial activity of thiazolo-, oxazolo-, and imidazolo[3,2-a][1,8]naphthyridinecarboxylic acids. J. Med. Chem. 1990, 33, 2012−2015. (18) Suryawanshi, S. N.; Pandey, S.; Rashmirathi; Bhatt, B. A.; Gupta, S. Chemotherapy of leishmaniasis Part VI: Synthesis and bioevaluation of some novel terpenyl S,N- and N,N-acetals. Eur. J. Med. Chem. 2007, 42, 511−516. (19) Abdelhalim, M. M.; El-Saidi, M. M. T.; Rabie, S. T.; Elmegeed, G. A. Synthesis of novel steroidal heterocyclic derivatives as antibacterial agents. Steroids 2007, 72, 459−465. (20) (a) Li, M.; Shao, P.; Wang, S.-W.; Kong, W.; Wen, L.-R. Four-component cascade heteroannulation

of

heterocyclic

ketene

aminals:

synthesis

of

functionalized

tetrahydroimidazo[1,2-a]pyridine derivatives. J. Org. Chem. 2012, 77, 8956–8967. (b) Wang, BQ.; Zhang, C.-H.; Tian, X.-X.; Lin, J.; Yan, S.-J. Cascade reaction of isatins with 1,1enediamines: synthesis of multisubstituted quinoline-4-carboxamides. Org. Lett. 2018, 20, 660– 663. (c) Zhang, C.-H.; Huang, R.; Hu, X.-M.; Lin, J.; Yan, S.-J. Three-component site-selective synthesis of highly substituted 5H-chromeno-[4,3-b]pyridines. J. Org. Chem. 2018, 83, 4981– 4989. (d) Du, X.-X.; Huang, R.; Yang, C.-L.; Lin, J.; Yan, S.-J. Synthesis and evaluation of the antitumor activity of highly functionalised pyridin-2-ones and pyrimidin-4-ones. RSC Adv. 2017, 7, 40067–40073. (21) Baylis, A. B.; Hillman, M. E. D. Acrylic compounds. Ger. 2155113. 1972. (22) (a) Deb I.; Dodwal, M.; Moin, S. M.; Namboothiri, I. N. N. Hydroxyalkylation of conjugated nitroalkenes with activated nonenolizable carbonyl compounds. Org. Lett. 2006, 8, 1201−1204. (b) Deb, I.; Shanbhag, P.; Mobin, S. M.; Namboothiri, I. N. N. Morita–Baylis– Hillman reactions between conjugated nitroalkenes or nitrodienes and carbonyl compounds. Eur. J. Org. Chem. 2009, 4091–4101. (c) Kuan, H.-H.; Reddy, R. J.; Chen, K. An efficient Morita–


33


Page 34 of 35

Baylis–Hillman reaction for the synthesis of multifunctional 2-hydroxy-3-nitrobut-3-enoate derivatives. Tetrahedron 2010, 66, 9875–9879. (23) (a) Nair, D. K.; Kumar, T.; Namboothiri, I. N. N. α-Functionalization of nitroalkenes and its applications in organic synthesis. Synlett 2016, 27, 2425–2442. (b) Satham, L.; Namboothiri, I. N. N. (3+3) Annulation of nitroallylic acetates with stabilized sulfur ylides for the synthesis of 2aryl terephthalates. J. Org. Chem. 2018, 83, 9471–9477. (24) (a) Liu, J.; Yan, S.-J.; Cao, Z.-M.; Cui, S.-S.; Liu, J. Synthesis of bicyclic 2-pyridones by regioselective annulations of heterocyclic ketene aminals with anhydrides. RSC Adv. 2016, 6, 103057–103064. (b) Liu, J.; Zhang, H.-R.; Lin, X.-R. Yan, S.-J.; Lin, J. Catalyst-free cascade reaction of heterocyclic ketene aminals with N-substituted maleimide to synthesise bicyclic pyrrolidinone derivatives. RSC Adv. 2014, 4, 27582–27590. (c) Chen, L.; Huang, R.; Du, X.-X.; Yan, S.-J.; Lin, J. One-pot synthesis of highly functionalized bicyclic imidazopyridinium derivatives in ethanol. ACS Sustainable Chem. Eng. 2017, 5, 1899−1905. (d) Liu, J.; Wang, Y.L.; Zhang, J.-H.; Yang, J.-S.; Mou, H.-C.; Lin, J.; Yan, S.-J. Phosphatase CDC25B inhibitors produced by basic alumina-supported one-pot gram-scale synthesis of fluorinated 2-alkylthio-4aminoquinazoolines using microwave irradiation. ACS Omega 2018, 3, 4534−4544. (25) Mendiola, J.; Castellote, I.; Alvarez-Builla, J.; Fernandez-Gadea, J.; Gomez, A.; Vaquero, J. J. Palladium-catalyzed arylation and heteroarylation of azolopyrimidines. J. Org. Chem. 2006, 71, 1254–1257. (26) (a) Nair, D. K.; Mobin, S. M.; Namboothiri, I. N. N. Synthesis of imidazopyridines from the Morita–Baylis–Hillman acetates of nitroalkenes and convenient access to Alpidem and Zolpidem. Org. Lett. 2012, 14, 4580–4583. (b) Huang, W.-Y.; Chen, Y.-C.; Chen, K. Efficient synthesis of tetrasubstituted furans from nitroallylic acetates and 1,3‐dicarbonyl/α‐activating


34

Page 35 of 35 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 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


ketones by Feist–Bénary addition–elimination. Chem. Asian J. 2012, 7, 688–691. (27) Reddy, R. J.; Chen, K. Highly efficient organocatalytic kinetic resolution of activated nitroallylic acetates with aldehydes via conjugate addition−elimination. Org. Lett. 2011, 13, 1458–1461. (28) (a) Mertens, H.; Troschütz, R.; Roth, H. J. Synthese primärer nitroketenaminale. Arch. Pharm. 1986, 319, 161−167. (b) Kenda, B.; Quesnel, Y.; Ates, A.; Michel, P.; Turet, L.; Mercier, J. 2-Oxo-1-Pyrrolidine derivatives, processes for preparing them and their uses. WO 2006128693 A2, 2006. (29) (a) Huang, Z.-T.; Wang, M.-X. A new route to 3H-1,5-benzodiazepines and heterocylic ketene aminals from benzoyl substituted ketene dithioacetals and diamines. Synthesis 1992, 12, 1273–1276. (b) Li, Z.-J.; Smith, C. D. The synthesis of fluoroheterocyclic ketene aminals. Synth. Commun. 2001, 31, 527–533.


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