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Mar 28, 2017 - Sciences of Guangxi Normal University, Guilin 541004, People's Republic of China. •S Supporting Information. ABSTRACT: A simple and ...
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Catalyst-Free Synthesis of Pyrrolo[1,2‑a]quinolines via Dehydration/ [3 + 2] Cycloaddition Directly from 2‑Methylquinolines, Aldehydes, and Alkynoates Fu-song Wu,†,‡,§ Hai-yuan Zhao,‡,§ Yan-li Xu,† Kun Hu,‡ Ying-ming Pan,*,‡ and Xian-li Ma*,† †

College of Pharmacy, Guilin Medical University, Guilin 541004, People’s Republic of China State Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources, School of Chemistry and Pharmaceutical Sciences of Guangxi Normal University, Guilin 541004, People’s Republic of China

‡

S Supporting Information *

ABSTRACT: A simple and efficient catalyst-free synthesis of pyrrolo[1,2-a]quinoline derivatives from 2-methylquinolines, aldehydes, and alkynoates via dehydration/[3 + 2] cycloaddition has been developed. The reaction conditions are tolerant to air, and H2O is the only byproduct of this transformation, thus offering an environmentally benign process with a wide range of potential applications in organic synthesis and medicinal chemistry.

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INTRODUCTION

RESULTS AND DISCUSSION For suitable conditions for this reaction to be identified, 2methylquinoline (1a), benzaldehyde (2a), and diethylbut-2ynedioate (3a) were chosen as model substrate, and a series of solvents were screened as shown in Table 1. Initially, a mixture of 2-methylquinoline (1a) and benzaldehyde (2a) were placed in DMSO at 140 °C overnight; then, diethylbut-2-ynedioate (3a) was added, and the mixture was stirred at 80 °C for another 8 h, giving a trace amount of desired product 4a (Table 1, entry 1). When this reaction was performed in other solvents such as chlorobenzene (PhCl), toluene, THF, EtOH, and DCE, the yield of desired product 4a was increased (Table 1, entries 2−6), and 4a was isolated in 30% yield with PhCl as solvent (Table 1, entry 2). Subsequently, we used PhCl as solvent and raised the temperature to 100 °C in the “second step” to afford 4a in 52% yield (Table 1, entry 7). The desired product 4a was obtained in 63 and 70% as the reaction was performed at 110 and 120 °C, respectively (Table 1, entries 8 and 9). In addition, we found that the yield of 4a was up to 88% when the amount of 3a was increased to 2 equiv, whereas no obvious improvement in yield could be observed as the amount of 3a was increased to 3 equiv (Table 1, entries 10−12). This transformation in the presence of other metal-catalysts such as Cu(OTf)2, InCl3, Ce(OTf)3, Sc(OTf)3, Pd(OAc)2, and Ni(OAc)2·4H2O in PhCl gave desired product 4a in very lower yield (for details, see SI). Therefore, the optimal conditions for this transformation were PhCl as solvent and stirring at 140 °C

Nitrogen-containing heterocyclic compounds are ubiquitous in natural molecules1 and exhibit a wide array of biological activities.2 Among various N-heterocycles, pyrrolo[1,2-a]quinoline derivatives have received much attention for their unique properties in functional materials3 and biological activities4 as well as in natural products5 (Scheme 1). Because of their unique biological activity-wide applications, functionalized pyrrolo[1,2-a]quinolines have elicited considerable synthetic interest, and a variety of synthetic routes have been established.6 Many transition metals such as Pd,7 Cu,8 Cu/Pd,9 Rh,10 Ir,11 Pt,12 Fe/Au,13 Sm,14 Ce,15 and so forth have been used as catalyst to prepare pyrrolo[1,2-a]quinolines derivatives; however, despite their potential utility, none of these procedures could directly provide the final products with a low content of heavy metal impurities.16 For the use of transition metals to be avoided, I2,17 acid,18 and carbonates19 were used as additives to synthesize pyrrolo[1,2-a]quinolines derivatives. Although these reported methods have made a significant contribution to the preparation of pyrrolo[1,2a]quinolines, the development of an efficient, simple, and environmentally friendly protocol for the preparation of pyrrolo[1,2-a]quinolines is still needed. As our continuation of our efforts studying the conversion of alkynes to nitrogencontaining heterocycles,20 herein we wish to describe a highly efficient catalyst-free synthesis of pyrrolo[1,2-a]quinolines through dehydration/[3 + 2] cycloaddition directly from 2methylquinolines, aldehydes, and alkynoates, and the process is outlined in Scheme 2. © 2017 American Chemical Society

Received: February 5, 2017 Published: March 28, 2017 4289

DOI: 10.1021/acs.joc.7b00280 J. Org. Chem. 2017, 82, 4289−4296

Article

The Journal of Organic Chemistry Scheme 1. A Few Examples of Pyrrolo[1,2-a]quinoline-Containing Natural Products and Pharmaceuticals

With the optimal reaction conditions in hand, we next evaluated the substrate scope of this transformation, and the results are shown in Table 2. Gratifyingly, it was observed that a wide range of the aldehydes and acetylenedicarboxylates were well-tolerated, providing the corresponding pyrrolo[1,2-a]quinoline derivatives in good to excellent yields. The dimethylbut-2-ynedioate (3b) instead of diethylbut-2-ynedioate reacts with 2-methylquinoline (1a) and benzaldehyde (2a), producing the corresponding final product in 86% yield. Benzaldehyde bearing electron-donating substituents such as tBu, Me, Et, and MeO or electron-withdrawing groups such as F, Cl, CN, and CHO on the aryl ring were found to be suitable substrates for this reaction and afforded the corresponding pyrrolo[1,2-a]quinoline products (4c−4k) in good to excellent yields, which showed that the position of the substituents on the benzene ring did not affect the reaction significantly. Furthermore, a single crystal of product 4f was obtained by slow crystallization from ethyl alcohol, and its structure was diethyl 3-(4-cyanobenzyl)pyrrolo[1,2-a]quinoline-1,2-dicarboxylate, which was confirmed by single-crystal X-ray analysis.21 In addition, the 2-naphthaldehyde substrate worked smoothly to provide desired product 4l in 72% yield. Both furan-2carbaldehyde and thiophene-2-carbaldehyde showed high reactivities, giving the corresponding products 4m and 4n in 73 and 77% yields, respectively. Unfortunately, the reaction of 2-methylquinoline (1a), heptanal, and diethylbut-2-ynedioate under the standard conditions only gave a trace amount of the desired product. Moreover, the reaction of 2-methylquinoline (1a), 4-fluorobenzaldehyde, and methyl-4,4,4-trifluorobut-2ynoate as substrates under the standard conditions gave 90% yield of desired product 4o, which was confirmed unambiguously by X-ray diffraction analysis.22 It should be noted that ethyl-2-oxoacetate was also a good substrate for this transformation and provided desired product 4p in 87% yield. However, the terminal alkyne substrate such as ethyl propiolate treated with 2-methylquinoline and benzaldehyde under the standard conditions failed to afford the corresponding product. Additionally, we continued to study the 2-methylquinolines scopes for this reaction. The reaction of 5-chloro-2-methylquinoline, benzaldehyde, and diethyl but-2-ynedioate under the standard conditions afforded desired product 4q in 92% yield. Desired products 4r−4u were obtained in excellent yields with an electron-donating group (Me, EtO) or an electronwithdrawing group (F) at C-6 of 2-methylquinolines. The substrates 7-fluoro-2-methylquinoline and 7-chloro-2-methylquinoline also worked well for this transformation and provided desired products 4v and 4w in 65 and 77% yields, respectively. However, the 8-substituted 2-methylquinoline substrate, such as 8-methoxy-2-methylquinoline reacted with benzaldehyde and diethylbut-2-ynedioate under the standard conditions, failed to give the desired product. Moreover, the 3-

Scheme 2. Synthesis of Pyrrolo[1,2-a]quinolines Derivatives via Dehydration/[3 + 2] Cycloaddition Reaction

Table 1. Optimization of Reaction Conditionsa

entry

solvent

T (°C)

yield (%)b

1 2 3 4 5 6 7 8 9 10c 11d 12e 13f

DMSO PhCl toluene THF EtOH DCE PhCl PhCl PhCl PhCl PhCl PhCl PhCl

80 80 80 80 80 80 100 110 120 120 120 120 120

5 30 28 18 27 28 52 63 70 75 88 89 77

a Reaction conditions: In a 25 mL sealed tube, 1a (0.5 mmol) and 2a (0.6 mmol) were added in solvent (1 mL) and stirred at 140 °C overnight. Then, 3a (0.5 mmol) was added and stirred at the indicated temperature for another 8 h. bIsolated yields (based on 1a). c Compound 3a (0.75 mmol) was used. dCompound 3a (1 mmol) was used. eCompound 3a (1.5 mmol) was used. fReaction conditions: In a 100 mL sealed tube, 1a (5 mmol), 2a (6 mmol), and PhCl (3 mL) were stirred at 140 °C overnight, and then 3a (10 mmol) was added and stirred at 120 °C for another 8 h.

overnight, and then adding 3a (2 equiv) to the reaction mixture at 120 °C and stirring for another 8 h. Moreover, the reaction was scalable and practical because a satisfactory yield (77%) could be obtained when the reaction was performed on a 5 mmol scale (Table 1, entry 13). 4290

DOI: 10.1021/acs.joc.7b00280 J. Org. Chem. 2017, 82, 4289−4296

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The Journal of Organic Chemistry Table 2. Synthesis of Pyrrolo[1,2-a]quinolines Derivativesa,b

Reaction conditions: In a 25 mL sealed tube, 1a (0.5 mmol) and 2a (0.6 mmol) were added in PhCl (1 mL) and stirred at 140 °C overnight. Then, 3a (1.0 mmol) was added and stirred at 120 °C for another 8 h. bIsolated yields (based on 1a). cToluene was used instead of PhCl.

a

(2a) should provide alkylated quinoline B,23 which upon dehydration gives rise to thermodynamically stable (E)-2styrylquinoline C.24 Then, 2-alkenylquinoline was reacted with acetylenedicarboxylate to generate intermediate D, which subsequent formed five-membered ring intermediate E with an exocyclic single band via the intramolecular nucleophilic addition of carbanion to CC double band process. Eventually, intermediate E underwent aromatization and a proton shift to furnish final product 4a.

methylbenzo[f ]quinoline substrate also proceeded smoothly and afforded desired product 4x in 55% yield. For insights into the mechanism to be obtained, several controlled experiments were conducted (Scheme 3). The reaction of 2-methylquinoline (1a) and 2-naphthaldehyde in PhCl stirred at 140 °C overnight gave the product (E)-2-(2(naphthalen-2-yl)vinyl)quinoline in 75% yield (eq 1). Subsequently, (E)-2-(2-(naphthalen-2-yl)vinyl)quinoline reacted with diethylbut-2-ynedioate (3a) in PhCl at 120 °C for 8 h, and desired product 4l was isolated in 70% yield (eq 2). The deuterium experiments of d3-1a, 2a, and 3b under standard conditions provided d-4b in 83% isolated yield (eq 3). Furthermore, the reaction of (E)-2-styrylquinoline and diethylbut-2-ynedioate (3a) in a mixture of anhydrous PhCl/ D2O (v/v = 10:1) at 120 °C for 8 h gave the desired products of 4a and d-4a in 35 and 0% yields, respectively (eq 4). On the basis of the above results, a possible mechanism is proposed in Scheme 4. At first, enamine intermediate A was generated from 1a via the requisite disruption of aromaticity. Subsequently, heteroene reaction between A and benzaldehyde

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CONCLUSIONS

In summary, we have developed an efficient “two step, one-pot” catalyst-free approach to pyrrolo[1,2-a]quinoline derivatives through a dehydration/[3 + 2] cycloaddition directly from 2methylquinolines, aldehydes, and alkynoates. The reaction conditions are tolerant to air, and the use of easily available starting materials, a wide range of substrates, exceptional functional group tolerance, and operational simplicity make it an attractive way to access pyrrolo[1,2-a]quinolines derivatives, 4291

DOI: 10.1021/acs.joc.7b00280 J. Org. Chem. 2017, 82, 4289−4296

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The Journal of Organic Chemistry Scheme 3. Control Experiments

Scheme 4. Plausible Mechanism

General Experimental Procedure for Synthesis of Pyrrolo[1,2-a]quinoline Derivatives 4. The 2-methylquinolines (0.5 mmol) and aldehydes (0.6 mmol) were dissolved with PhCl (1 mL) in 25 mL of tube sealing. The reaction mixture was stirred at 140 °C overnight. Subsequently, alkynoates (1 mmol) were added, and the reaction mixture was stirred at 120 °C for another 8 h (monitored by TLC). Upon completion, the crude product was cooled to room temperature, and PhCl was removed under vacuum. The crude product was purified by column chromatography on silica gel (300− 400 mesh) to afford the pure product. The crude product was purified by column chromatography on silica gel (300−400 mesh), using the petroleum ether/ethyl acetate (v/v = 50:1) to afford the pure product. Diethyl 3-Benzylpyrrolo[1,2-a]quinoline-1,2-dicarboxylate (4a).25 White solid (176.51 mg, 88%); mp 87−88 °C; 1H NMR (500 MHz, CDCl3) δ 7.86 (d, J = 8.5 Hz, 1H), 7.65 (dd, J = 7.8, 1.4 Hz, 1H), 7.49−7.45 (m, 1H), 7.41−7.37 (m, 1H), 7.31 (d, J = 9.4 Hz, 1H), 7.22 (dt, J = 15.1, 7.2 Hz, 4H), 7.15 (t, J = 7.0 Hz, 1H), 7.08 (d, J = 9.4 Hz, 1H), 4.55 (q, J = 7.2 Hz, 2H), 4.36 (s, 2H), 4.28 (q, J = 7.1 Hz, 2H),

and further studies on the applications in drug design are currently ongoing in our laboratory.

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EXPERIMENTAL SECTION

General Information. All of the reactions were carried out in tube sealing under an air atmosphere unless otherwise indicated. Column chromatography was performed on silica gel (300−400 mesh). NMR spectra were obtained using a Bruker Avance 500 spectrometer (1H at 500 MHz and 13C at 125 MHz) or Bruker Avance 400 spectrometer (1H at 400 MHz and 13C at 100 MHz). High-resolution mass spectra (HRMS) were recorded on an Exactive Mass Spectrometer (Thermo Scientific, USA) or QSTAR Elite equipped with APCI or ESI ionization source and Thermo Scientific Exactive Orbitrap mass analyzer. Materials. Unless stated otherwise, commercial reagents were used without further purification. All reagents were weighed and handled in air at room temperature. 4292

DOI: 10.1021/acs.joc.7b00280 J. Org. Chem. 2017, 82, 4289−4296

Article

The Journal of Organic Chemistry 1.45 (t, J = 7.2 Hz, 3H), 1.27 (t, J = 7.1 Hz, 3H) ppm; 13C NMR (125 MHz, CDCl3) δ 164.9, 164.7, 141.1, 133.2, 131.0, 129.1, 128.4, 128.3, 128.1, 126.0, 125.7, 125.3, 122.0,121.7, 119.9, 117.1, 116.7, 115.8, 62.5, 60.8, 30.1, 14.3, 14.1 ppm; HRMS (m/z) (ESI) calcd for C25H24NO4 402.1700 [M + H+], found 402.1693. Dimethyl 3-Benzylpyrrolo[1,2-a]quinoline-1,2-dicarboxylate (4b).25 White solid (160.45 mg, 86%); mp 89−90 °C; 1H NMR (400 MHz, CDCl3) δ 7.78 (d, J = 8.5 Hz, 1H), 7.58 (dd, J = 7.8, 1.4 Hz, 1H), 7.46−7.38 (m, 1H), 7.36−7.30 (m, 1H), 7.25−7.21 (m, 1H), 7.21−7.16 (m, 1H), 7.15−7.10 (m, 1H), 7.02 (d, J = 9.4 Hz, 1H), 4.32 (s, 1H), 4.06 (s, 1H), 3.80 (s, 1H) ppm; 13C NMR (100 MHz, CDCl3) δ 165.3, 165.0, 141.0, 133.0, 131.0, 129.1, 128.4, 128.2, 128.2, 125.9, 125.6, 125.3, 121.7, 121.6, 119.7, 116.9, 116.5, 115.9, 53.2, 51.8, 30.0 ppm; HRMS (m/z) (ESI) calcd for C23H19NNaO4 396.1206 [M +Na+], found 396.1205. Diethyl 3-(4-(tert-Butyl)benzyl)pyrrolo[1,2-a]quinoline-1,2-dicarboxylate (4c). White solid (173.75 mg, 73%); mp 86−87 °C; 1H NMR (400 MHz, CDCl3) δ 7.81 (d, J = 8.5 Hz, 1H), 7.54 (dd, J = 7.8, 1.2 Hz, 1H), 7.42−7.37 (m, 1H), 7.30 (dd, J = 11.0, 3.9 Hz, 1H), 7.24 (dd, J = 10.2, 9.0 Hz, 3H), 7.11 (d, J = 8.3 Hz, 2H), 6.98 (d, J = 9.4 Hz, 1H), 4.51 (q, J = 7.2 Hz, 2H), 4.29−4.23 (m, 4H), 1.41 (t, J = 7.2 Hz, 3H), 1.26−1.21 (m, 12H) ppm; 13C NMR (100 MHz, CDCl3) δ 164.8, 164.7,148.6, 138.0, 133.1, 130.9, 129.0, 127.9, 127.9,125.6, 125.2, 125.1,121.9, 121.5, 120.0, 117.1, 116.7, 116.0, 62.4, 60.7, 34.3, 31.4, 29.5, 14.2, 14.0 ppm; HRMS (m/z) (ESI) calcd for C29H32NO4 458.2326 [M + H+], found 458.2319. Diethyl 3-(4-Methoxybenzyl)pyrrolo[1,2-a]quinoline-1,2-dicarboxylate (4d). White solid (150.91 mg, 70%); mp 75−76 °C; 1H NMR (500 MHz, CDCl3) δ 7.88 (d, J = 8.5 Hz, 1H), 7.67 (dd, J = 7.8, 1.4 Hz, 1H), 7.51−7.47 (m, 1H), 7.43−7.39 (m, 1H), 7.33 (d, J = 9.4 Hz, 1H), 7.14 (d, J = 8.7 Hz, 2H), 7.11 (d, J = 9.4 Hz, 1H), 6.82−6.81 (m, 1H), 6.79 (t, J = 2.6 Hz, 1H), 4.57 (q, J = 7.2 Hz, 2H), 4.32 (p, J = 7.2 Hz, 4H), 3.78 (s, 3H), 1.48 (t, J = 7.2 Hz, 3H), 1.31 (t, J = 7.1 Hz, 3H) ppm; 13C NMR (125 MHz, CDCl3) δ 164.7, 164.6, 157.8, 133.1, 133.1,130.8, 129.1, 129.0, 128.0, 125.6, 125.1, 121.8, 121.5, 119.8, 117.0, 116.7, 116.2, 113.7, 62.4, 60.7, 55.3, 29.1, 14.2, 14.0 ppm; HRMS (m/z) (ESI) calcd for C26H26NO5 432.1805 [M + H+], found 432.1803. Diethyl 3-(4-Fluorobenzyl)pyrrolo[1,2-a]quinoline-1,2-dicarboxylate (4e). White solid (186.52 mg, 89%); mp 107−108 °C; 1H NMR (500 MHz, CDCl3) δ 7.85 (d, J = 8.5 Hz, 1H), 7.64 (d, J = 7.7 Hz, 1H), 7.50−7.45 (m, 1H), 7.38 (t, J = 7.5 Hz, 1H), 7.27 (t, J = 5.6 Hz, 1H), 7.15 (dd, J = 8.6, 5.5 Hz, 2H), 7.08 (d, J = 9.4 Hz, 1H), 6.95− 6.89 (m, 2H), 4.56 (q, J = 7.2 Hz, 2H), 4.33−4.26 (m, 4H), 1.46 (t, J = 7.2 Hz, 3H), 1.28 (t, J = 7.1 Hz, 3H) ppm; 13C NMR (125 MHz, CDCl3) δ 164.9, 164.5, 162.3, 160.4, 136.7, 136.7, 133.1, 130.8, 129.6, 129.6, 129.1, 128.1, 125.7, 125.3, 122.1, 121.8, 119.6, 116.8, 116.7, 115.7, 115.1, 115.0, 62.6, 60.8, 29.3, 14.3, 14.1 ppm; HRMS (m/z) (ESI) calcd for C25H22FNO4 419.1602 [M + H+], found 420.1606. Diethyl 3-(4-Cyanobenzyl)pyrrolo[1,2-a]quinoline-1,2-dicarboxylate (4f). White solid (198.16 mg, 93%); mp 98−100 °C; 1H NMR (500 MHz, CDCl3) δ 7.84 (d, J = 8.6 Hz, 1H), 7.66 (d, J = 7.7 Hz, 1H), 7.54−7.47 (m, 3H), 7.41 (t, J = 7.5 Hz, 1H), 7.29 (d, J = 8.3 Hz, 2H), 7.25 (d, J = 9.5 Hz, 1H), 7.12 (d, J = 9.4 Hz, 1H), 4.56 (q, J = 7.2 Hz, 2H), 4.41 (s, 2H), 4.26 (q, J = 7.1 Hz, 2H), 1.46 (t, J = 7.2 Hz, 3H), 1.25 (t, J = 7.2 Hz, 3H) ppm; 13C NMR (125 MHz, CDCl3) δ 164.9, 164.2, 146.8, 133.1, 132.2, 130.8, 129.2, 129.1, 128.4, 125.6, 125.5, 122.6, 122.1, 119.2, 118.9, 116.5, 116.4, 114.1, 109.8, 62.7, 60.8, 30.3, 14.3, 14.1 ppm; HRMS (m/z) (ESI) calcd for C26H23N2O4 427.1652 [M + H+], found 427.1652. Dimethyl 3-(4-Formylbenzyl)pyrrolo[1,2-a]quinoline-1,2-dicarboxylate (4g). White solid (184.52 mg, 92%); mp 110−111 °C; 1H NMR (400 MHz, CDCl3) δ 9.90 (s, 1H), 7.77 (d, J = 8.5 Hz, 1H), 7.72 (d, J = 8.0 Hz, 2H), 7.59 (d, J = 7.6 Hz, 1H), 7.45 (t, J = 7.5 Hz, 1H), 7.34 (dd, J = 18.5, 7.7 Hz, 3H), 7.21 (d, J = 9.4 Hz, 1H), 7.04 (d, J = 9.4 Hz, 1H), 4.36 (s, 2H), 4.07 (s, 3H), 3.79 (s, 3H) ppm; 13C NMR (100 MHz, CDCl3) δ 191.9, 165.2, 164.6, 148.4, 134.6, 132.9, 130.9, 129.8, 129.1, 128.8, 128.3, 125.5, 125.4, 122.0, 121.9, 119.0, 116.4, 116.3, 114.6, 53.3, 51.8, 30.2 ppm; HRMS (m/z) (ESI) calcd for C24H20NO5 402.1336 [M + H+], found 402.1337.

Diethyl 3-(3-Methylbenzyl)pyrrolo[1,2-a]quinoline-1,2-dicarboxylate (4h). White solid (170.22 mg, 82%); mp 95−97 °C; 1H NMR (400 MHz, CDCl3) δ 7.91 (d, J = 8.6 Hz, 1H), 7.54 (d, J = 7.8 Hz, 1H), 7.45 (t, J = 7.8 Hz, 1H), 7.32 (t, J = 7.5 Hz, 1H), 7.25 (d, J = 9.5 Hz, 1H), 7.19 (t, J = 7.5 Hz, 1H), 7.09 (d, J = 10.5 Hz, 2H), 7.02 (d, J = 7.4 Hz, 1H), 6.97 (d, J = 9.4 Hz, 1H), 4.63 (q, J = 7.2 Hz, 2H), 4.38 (dd, J = 15.5, 8.3 Hz, 4H), 2.33 (s, 3H), 1.52 (t, J = 7.2 Hz, 3H), 1.35 (t, J = 7.1 Hz, 3H) ppm; 13C NMR (100 MHz, CDCl3) δ 164.5, 164.4, 140.8, 137.5, 132.8, 130.7, 128.8, 128.7, 128.0, 127.7, 126.5, 125.4, 125.2, 124.9, 121.7, 121.3, 119.7, 116.7, 116.3, 115.6, 62.2, 60.5, 29.7, 21.3, 14.0, 13.8 ppm; HRMS (m/z) (ESI) calcd for C26H26NO4 416.1856 [M + H+], found 416.1855. Diethyl 3-(3-Chlorobenzyl)pyrrolo[1,2-a]quinoline-1,2-dicarboxylate (4i). White solid (189.28 mg, 87%); mp 102−103 °C; 1H NMR (400 MHz, CDCl3) δ 7.86 (d, J = 8.6 Hz, 1H), 7.61 (dd, J = 7.8, 1.4 Hz, 1H), 7.46 (ddd, J = 8.7, 7.3, 1.6 Hz, 1H), 7.38−7.34 (m, 1H), 7.26−7.19 (m, 2H), 7.14 (t, J = 4.6 Hz, 2H), 7.09−7.02 (m, 2H), 4.57 (q, J = 7.2 Hz, 2H), 4.35−4.26 (m, 4H), 1.47 (t, J = 7.2 Hz, 3H), 1.29 (t, J = 7.1 Hz, 3H) ppm; 13C NMR (100 MHz, CDCl3) δ 164.8, 164.4, 143.2, 134.1, 133.0, 130.8, 129.5, 129.1, 128.3, 128.1, 126.5, 126.1, 125.6, 125.2, 122.2, 121.8, 119.4, 116.6, 116.5, 114.8, 62.5, 60.8, 29.7, 14.2, 14.0 ppm; HRMS (m/z) (ESI) calcd for C25H23ClNO4 436.1310 [M + H+], found 436.1308. Diethyl 3-(2-Ethylbenzyl)pyrrolo[1,2-a]quinoline-1,2-dicarboxylate (4j). White solid (150.22 mg, 70%); mp 89−91 °C; 1H NMR (400 MHz, CDCl3) δ 7.86 (d, J = 8.6 Hz, 1H), 7.46 (d, J = 7.7 Hz, 1H), 7.41−7.35 (m, 1H), 7.24 (t, J = 7.4 Hz, 1H), 7.15 (dd, J = 5.9, 1.6 Hz, 1H), 7.08 (td, J = 7.4, 0.9 Hz, 1H), 6.98−6.92 (m, 2H), 6.83 (d, J = 9.5 Hz, 1H), 6.74 (d, J = 7.4 Hz, 1H), 4.55 (q, J = 7.2 Hz, 2H), 4.24 (s, 2H), 4.19 (q, J = 7.1 Hz, 2H), 2.76 (q, J = 7.5 Hz, 2H), 1.43 (t, J = 7.2 Hz, 3H), 1.27 (t, J = 7.5 Hz, 3H), 1.12 (t, J = 7.1 Hz, 3H) ppm; 13 C NMR (100 MHz, CDCl3) δ 164.6, 164.3, 141.4, 138.1, 132.9, 130.9, 128.8 127.8, 127.7, 125.9, 125.7, 125.4, 124.9, 121.9, 121.2, 120.2, 116.7, 116.4, 114.7, 62.2, 60.4, 29.6, 26.6, 25.8, 14.4, 13.9 ppm; HRMS (m/z) (ESI) calcd for C27H28NO4 430.2013 [M + H+], found 430.2011. Diethyl 3-(2-Chlorobenzyl)pyrrolo[1,2-a]quinoline-1,2-dicarboxylate (4k). White solid (180.58 mg, 83%); mp 105−106 °C; 1H NMR (400 MHz, CDCl3) δ 7.88 (d, J = 8.6 Hz, 1H), 7.61 (d, J = 7.7 Hz, 1H), 7.51−7.45 (m, 1H), 7.38 (dd, J = 10.3, 3.8 Hz, 2H), 7.18 (d, J = 9.4 Hz, 1H), 7.10 (td, J = 7.6, 1.5 Hz, 1H), 7.06−7.01 (m, 2H), 6.83 (d, J = 6.6 Hz, 1H), 4.60 (q, J = 7.2 Hz, 2H), 4.41 (s, 2H), 4.23 (q, J = 7.1 Hz, 2H), 1.48 (t, J = 7.2 Hz, 3H), 1.17 (t, J = 7.1 Hz, 3H) ppm; 13 C NMR (100 MHz, CDCl3) δ 164.9, 164.4, 138.5, 133.6, 133.1, 131.2, 129.4, 129.1, 129.0, 128.1, 127.2, 126.7, 125.6, 125.3, 122.5, 121.7, 119.9, 116.8, 116.5, 113.7, 62.6, 60.7, 27.7, 14.0, 14.0 ppm; HRMS (m/z) (ESI) calcd for C25H23ClNO4 436.1310 [M + H+], found 436.1309. Diethyl 3-(Naphthalen-2-ylmethyl)pyrrolo[1,2-a]quinoline-1,2-dicarboxylate (4l). White solid (162.42 mg, 72%); mp 95−97 °C; 1H NMR (500 MHz, CDCl3) δ 7.88 (d, J = 8.6 Hz, 1H), 7.79−7.75 (m, 1H), 7.74−7.70 (m, 2H), 7.65 (dd, J = 7.8, 1.4 Hz, 1H), 7.57 (s, 1H), 7.50−7.46 (m, 1H), 7.40 (dtd, J = 13.9, 6.9, 1.6 Hz, 4H), 7.33 (d, J = 9.4 Hz, 1H), 7.09 (d, J = 9.4 Hz, 1H), 4.59−4.52 (m, 4H), 4.26 (q, J = 7.1 Hz, 2H), 1.46 (t, J = 7.2 Hz, 3H), 1.24 (t, J = 7.1 Hz, 3H) ppm; 13 C NMR (125 MHz, CDCl3) δ 164.9, 164.7, 138.7, 133.7, 133.2, 132.1, 131.2, 129.1, 128.1, 128.0, 127.7, 127.7, 127.3, 126.2, 126.0, 125.8, 125.3, 125.3, 122.1, 121.8, 120.0, 117.1, 116.8, 115.6, 62.6, 60.8, 30.3, 14.3, 14.1 ppm; HRMS (m/z) (ESI) calcd for C29H26NO4 452.1856 [M + H+], found 452.1850. Diethyl 3-(Furan-2-ylmethyl)pyrrolo[1,2-a]quinoline-1,2-dicarboxylate (4m). White solid (142.77 mg, 73%); mp 121−122 °C; 1H NMR (500 MHz, CDCl3) δ 7.83 (d, J = 8.5 Hz, 1H), 7.65 (dd, J = 7.7, 1.3 Hz, 1H), 7.48−7.44 (m, 1H), 7.41−7.34 (m, 2H), 7.27 (d, J = 1.0 Hz, 1H), 7.11 (d, J = 9.4 Hz, 1H), 6.23 (dd, J = 3.1, 1.9 Hz, 1H), 5.94−5.90 (m, 1H), 4.55 (q, J = 7.2 Hz, 2H), 4.33 (dd, J = 13.2, 6.1 Hz, 4H), 1.45 (t, J = 7.2 Hz, 3H), 1.33 (t, J = 7.1 Hz, 3H) ppm; 13C NMR (125 MHz, CDCl3) δ 164.9, 164.5, 154.6, 141.1, 133.1, 130.8, 129.1, 128.1, 125.7, 125.3, 122.1, 121.7, 119.3, 117.1, 116.6, 113.1, 4293

DOI: 10.1021/acs.joc.7b00280 J. Org. Chem. 2017, 82, 4289−4296

Article

The Journal of Organic Chemistry

4.54−4.45 (m, 4H), 4.33 (q, J = 7.1 Hz, 2H), 4.09 (q, J = 7.0 Hz, 2H), 1.43 (q, J = 7.2 Hz, 6H), 1.34 (t, J = 7.1 Hz, 3H) ppm; 13C NMR (100 MHz, CDCl3) δ 165.2, 164.4, 163.1, 160.7, 156.1, 135.5, 135.5, 130.9, 128.2, 128.1, 127.6, 126.9, 126.8, 126.7, 125.5, 125.5, 121.8, 121.3, 120.5, 118.6, 117.4, 117.3, 116.5, 114.4, 114.2, 113.4, 111.3, 64.0, 62.2, 60.9, 22.1, 22.1, 14.9, 14.4, 14.1 ppm; HRMS (m/z) (ESI) calcd for C27H26ClFNO5 498.1478 [M + H+], found 498.1478. Diethyl 3-Benzyl-7-fluoropyrrolo[1,2-a]quinoline-1,2-dicarboxylate (4u). White solid (180.23 mg, 86%); mp 107−109 °C; 1H NMR (400 MHz, CDCl3) δ 7.82 (dd, J = 9.3, 4.5 Hz, 1H), 7.26−7.08 (m, 8H), 6.92 (d, J = 9.4 Hz, 1H), 4.51 (q, J = 7.2 Hz, 2H), 4.30−4.23 (m, 4H), 1.42 (t, J = 7.2 Hz, 3H), 1.24 (t, J = 7.1 Hz, 3H) ppm; 13C NMR (100 MHz, CDCl3) δ 164.6, 160.7, 158.3, 140.9, 130.8, 129.6, 129.6, 128.4, 128.3, 127.4, 127.3, 126.0, 121.9, 120.8, 120.8, 120.4, 118.6, 118.6, 118.2, 116.3, 115.7, 115.5, 113.9, 113.7, 62.5, 60.8, 30.0, 14.2, 14.0 ppm; HRMS (m/z) (ESI) calcd for C25H23FNO4 420.1606 [M + H+], found 420.1604. Dimethyl 8-Fluoro-3-(4-methylbenzyl)pyrrolo[1,2-a]quinoline1,2-dicarboxylate(4v). White solid (131.67 mg, 65%); mp 97−99 °C; 1H NMR (500 MHz, CDCl3) δ 7.57 (dt, J = 8.2, 2.9 Hz, 2H), 7.24 (d, J = 9.4 Hz, 1H), 7.13−7.08 (m, 3H), 7.06 (d, J = 8.1 Hz, 2H), 7.02 (d, J = 9.5 Hz, 1H), 4.28 (s, 2H), 4.09 (s, 3H), 3.85 (s, 3H), 2.29 (s, 3H) ppm; 13C NMR (125 MHz, CDCl3) δ 165.0, 164.8, 162.7, 160.7, 137.7, 135.5, 133.8, 133.7, 131.2, 130.6, 130.6, 129.1, 128.1, 122.1, 122.1, 121.2, 121.2, 120.9, 116.3, 116.2, 116.1, 113.5, 113.3, 104.1, 103.9, 53.4, 51.9, 29.6, 21.0 ppm; HRMS (m/z) (ESI) calcd for C24H21FNO4 406.1449 [M + H+], found 406.1447. Diethyl 3-Benzyl-8-chloropyrrolo[1,2-a]quinoline-1,2-dicarboxylate (4w). White solid (167.53 mg, 77%); mp 98−100 °C; 1H NMR (400 MHz, CDCl3) δ 7.81 (d, J = 1.6 Hz, 1H), 7.44 (d, J = 8.4 Hz, 1H), 7.25 (dd, J = 8.4, 1.8 Hz, 1H), 7.21−7.08 (m, 6H), 6.90 (d, J = 9.4 Hz, 1H), 4.53 (q, J = 7.2 Hz, 2H), 4.25 (dd, J = 15.4, 8.2 Hz, 4H), 1.46 (t, J = 7.2 Hz, 3H), 1.23 (t, J = 7.1 Hz, 3H) ppm; 13C NMR (100 MHz, CDCl3) δ 164.4, 164.3, 140.8, 133.5, 133.5, 130.9, 129.9, 128.4, 128.2, 126.0, 125.5, 124.1, 122.1, 120.7, 120.5, 117.2, 116.9, 116.1, 62.7, 60.9, 30.0, 14.2, 14.0 ppm; HRMS (m/z) (ESI) calcd for C25H23ClNO4 436.1310 [M + H+], found 436.1306. Dimethyl 1-Benzylbenzo[f ]pyrrolo[1,2-a]quinoline-2,3-dicarboxylate (4x). White solid (116.37 mg, 55%); mp 105−106 °C; 1H NMR (500 MHz, CDCl3) δ 8.52 (d, J = 8.5 Hz, 1H), 8.06 (d, J = 9.7 Hz, 1H), 7.97 (d, J = 11.2 Hz, 3H), 7.71 (t, J = 7.3 Hz, 1H), 7.65−7.57 (m, 2H), 7.29 (dd, J = 11.0, 3.7 Hz, 4H), 7.20 (t, J = 6.7 Hz, 1H), 4.43 (s, 2H), 4.12 (s, 3H), 3.89 (s, 3H) ppm; 13C NMR (125 MHz, CDCl3) δ 165.4, 165.1, 141.0, 132.0, 131.2, 130.8, 130.1, 129.0, 128.8, 128.5, 128.4, 127.6, 126.4, 126.1, 123.0, 121.4, 121.0, 120.3, 117.2, 116.8, 116.6, 115.3, 53.2, 52.0, 30.3 ppm; HRMS (m/z) (ESI) calcd for C27H22NO4 424.1543 [M + H+], found 424.1540. Substep Synthesis of 4l. 2-Methylquinoline (1a, 1.0 mmol) and 2-naphthaldehyde (2l, 1.2 mmol) were dissolved with 1 mL of PhCl in 25 mL of tube sealing. The reaction mixture was stirred at 140 °C overnight and detected by TLC to confirm 1a was completely consumed, and then the PhCl was removed under vacuum. The crude product was purified by column chromatography on silica gel (300− 400 mesh) to afford the 2-(2-(naphthalen-2-yl)vinyl)quinolone in 75% yield. Subsequently, the 2-(2-(naphthalen-2-yl)vinyl)quinolone (0.5 mmol) was placed in a mixed solution of PhCl (1 mL) with diethylbut-2-ynedioate (3a, 1.0 mmol), and the reaction mixture was stirred at 120 °C for 8 h. Then, the PhCl was removed under vacuum. The crude product was purified by column chromatography on silica gel (300−400 mesh) to afford product 4l in 70% yield. The product was further identified by 1H and 13C NMR. 2-(2-(Naphthalen-2-yl)vinyl)quinoline. Light yellow solid; mp 99− 101 °C; 1H NMR (500 MHz, CDCl3) δ 8.12 (t, J = 7.7 Hz, 2H), 7.99 (s, 1H), 7.85 (dt, J = 5.8, 3.8 Hz, 5H), 7.79 (d, J = 7.5 Hz, 1H), 7.74− 7.69 (m, 2H), 7.56−7.46 (m, 4H) ppm; 13C NMR (125 MHz, CDCl3) δ 156.1, 148.4, 136.5, 134.7, 134.2, 133.7, 133.6, 129.9, 129.4, 129.3, 128.6, 128.4, 128.2, 127.9, 127.6, 127.5, 126.6, 126.5, 126.3, 123.8, 119.4 ppm; HRMS (m/z) (ESI) calcd for C21H16N 282.1277 [M + H+], found 282.1275.

110.4, 105.6, 62.6, 60.8, 23.4, 14.3, 14.1 ppm; HRMS (m/z) (ESI) calcd for C23H22NO5 392.1492 [M + H+], found 392.1492. Diethyl3-(Thiophen-2-ylmethyl)pyrrolo[1,2-a]quinoline-1,2-dicarboxylate (4n). White solid (156.75 mg, 77%); mp 108−109 °C; 1H NMR (500 MHz, CDCl3) δ 7.82 (d, J = 8.6 Hz, 1H), 7.60 (d, J = 7.8 Hz, 1H), 7.47−7.42 (m, 1H), 7.38−7.30 (m, 2H), 7.07 (dt, J = 11.5, 5.7 Hz, 2H), 6.87 (dd, J = 5.1, 3.5 Hz, 1H), 6.80 (dd, J = 3.4, 1.0 Hz, 1H), 4.57 (q, J = 7.2 Hz, 2H), 4.52 (s, 2H), 4.36 (q, J = 7.1 Hz, 2H), 1.46 (t, J = 7.2 Hz, 3H), 1.35 (t, J = 7.1 Hz, 3H) ppm; 13C NMR (125 MHz, CDCl3) δ 164.9, 164.4, 144.4, 133.0, 130.4, 129.0, 128.0, 126.7, 125.5, 125.2, 124.4, 123.4, 122.2, 121.6, 118.8, 116.7, 116.4, 115.5, 62.5, 60.8, 24.6, 14.3, 14.0 ppm; HRMS (m/z) (ESI) calcd for C23H22NO4S 408.1264 [M + H+], found 408.1256. Ethyl 3-(4-Fluorobenzyl)-1-(trifluoromethyl)pyrrolo[1,2-a]quinoline-2-carboxylate (4o). White solid (186.81 mg, 90%); mp 106−108 °C; 1H NMR (400 MHz, CDCl3) δ 8.17 (d, J = 8.6 Hz, 1H), 7.68 (d, J = 7.7 Hz, 1H), 7.58 (t, J = 7.8 Hz, 1H), 7.44 (t, J = 7.4 Hz, 1H), 7.27 (t, J = 6.6 Hz, 1H), 7.17 (dd, J = 16.9, 8.1 Hz, 3H), 6.94 (t, J = 8.5 Hz, 2H), 4.34 (q, J = 7.1 Hz, 2H), 4.20 (s, 2H), 1.32 (t, J = 7.1 Hz, 3H) ppm; 13C NMR (100 MHz, CDCl3) δ 165.2, 162.7, 160.3, 136.0, 136.0, 133.4, 132.8, 129.8, 129.7, 129.0, 128.5, 125.7, 125.5, 125.2, 125.2, 123.4, 123.3, 120.8, 118.4, 118.3, 118.3, 118.2, 116.3, 115.4, 115.2, 115.1, 61.7, 29.0, 14.1 ppm; HRMS (m/z) (ESI) calcd for C23H18F4NO2 416.1268 [M + H+], found 416.1268. Dimethyl 3-(2-Ethoxy-2-oxoethyl)pyrrolo[1,2-a]quinoline-1,2-dicarboxylate (4p). White solid (160.57 mg, 87%); mp 141−142 °C; 1 H NMR (400 MHz, CDCl3) δ 7.71 (d, J = 8.5 Hz, 1H), 7.59 (d, J = 7.7 Hz, 1H), 7.43 (t, J = 7.8 Hz, 1H), 7.34 (t, J = 7.5 Hz, 1H), 7.25 (d, J = 9.5 Hz, 1H), 7.06 (d, J = 9.5 Hz, 1H), 4.15 (q, J = 7.1 Hz, 2H), 4.07 (s, 3H), 3.96 (s, 2H), 3.88 (s, 3H), 1.24 (t, J = 7.1 Hz, 3H) ppm; 13 C NMR (100 MHz, CDCl3) δ 171.3, 165.3, 164.6, 132.8, 130.9, 129.1, 128.2, 125.4, 125.3, 122.0, 121.9, 118.9, 116.4, 116.2, 109.7, 60.9, 53.3, 51.8, 30.5, 14.3 ppm; HRMS (m/z) (ESI) calcd for C20H20NO6 370.1285 [M + H+], found 370.1283. Diethyl 3-Benzyl-6-chloropyrrolo[1,2-a]quinoline-1,2-dicarboxylate (4q). White solid (200.16 mg, 92%); mp 118−120 °C; 1H NMR (400 MHz, CDCl3) δ 7.70 (d, J = 8.6 Hz, 1H), 7.45 (d, J = 9.8 Hz, 1H), 7.37 (d, J = 7.1 Hz, 1H), 7.29 (dd, J = 9.1, 3.1 Hz, 2H), 7.19−7.06 (m, 5H), 4.47 (q, J = 7.2 Hz, 2H), 4.28 (s, 2H), 4.23 (q, J = 7.1 Hz, 2H), 1.38 (t, J = 7.2 Hz, 3H), 1.21 (t, J = 7.1 Hz, 3H) ppm; 13 C NMR (100 MHz, CDCl3) δ 164.5, 164.4, 140.8, 134.2, 133.0, 130.8, 128.4, 128.3, 127.7, 126.0, 125.9, 123.7, 122.5, 120.8, 118.2, 117.4, 116.4, 115.6, 62.6, 60.9, 30.0, 14.2, 14.0 ppm; HRMS (m/z) (ESI) calcd forC25H23ClNO4436.1310 [M + H+], found 436.1311. Diethyl 3-(4-Chlorobenzyl)-7-methylpyrrolo[1,2-a]quinoline-1,2dicarboxylate (4r). White solid (197.63 mg, 88%); mp 101−103 °C; 1H NMR (400 MHz, CDCl3) δ 7.75 (d, J = 8.7 Hz, 1H), 7.41 (s, 1H), 7.28 (dd, J = 8.7, 1.8 Hz, 1H), 7.23−7.18 (m, 3H), 7.12 (d, J = 8.5 Hz, 2H), 7.01 (d, J = 9.5 Hz, 1H), 4.55 (q, J = 7.2 Hz, 2H), 4.32− 4.26 (m, 4H), 2.44 (s, 3H), 1.46 (t, J = 7.2 Hz, 3H), 1.28 (t, J = 7.1 Hz, 3H) ppm; 13C NMR (100 MHz, CDCl3) δ 164.9, 164.5, 139.7, 135.1, 131.6, 131.1, 130.7, 129.6, 129.3, 128.9, 128.4, 125.6, 121.9, 121.7, 119.2, 116.6, 116.4, 115.1, 62.5, 60.7, 29.4, 20.9, 14.3, 14.1 ppm; HRMS (m/z) (ESI) calcd for C26H25ClNO4 450.1467 [M + H+], found 450.1468. Diethyl 3-(3-Cyanobenzyl)-7-ethoxypyrrolo[1,2-a]quinoline-1,2dicarboxylate (4s). White solid (211.58 mg, 90%); mp 85−87 °C; 1 H NMR (500 MHz, CDCl3) δ 7.75 (d, J = 10.1 Hz, 1H), 7.47 (s, 1H), 7.43 (d, J = 7.7 Hz, 2H), 7.30 (t, J = 7.7 Hz, 1H), 7.21 (d, J = 9.4 Hz, 1H), 7.05 (dt, J = 19.0, 6.1 Hz, 3H), 4.54 (q, J = 7.2 Hz, 2H), 4.34 (s, 2H), 4.27 (q, J = 7.1 Hz, 2H), 4.09 (q, J = 6.9 Hz, 2H), 1.45 (td, J = 7.0, 3.1 Hz, 6H), 1.26 (t, J = 7.1 Hz, 3H) ppm; 13C NMR (125 MHz, CDCl3) δ 164.9, 164.3, 156.2, 142.7, 132.9, 131.8, 130.3, 129.7, 129.1, 127.3, 126.9, 122.0, 121.9, 119.2, 118.3, 117.8, 116.8, 116.7, 114.2, 112.2, 111.6, 64.0, 62.6, 60.7, 29.6, 14.9, 14.2, 14.1 ppm; HRMS (m/z) (ESI) calcd for C28H26N2NaO5 493.1734 [M+Na+], found 493.1735. Diethyl 3-(2-Chloro-6-fluorobenzyl)-7-ethoxypyrrolo[1,2-a]quinoline-1,2-dicarboxylate (4t). White solid (218.75 mg, 88%); mp 87−89 °C; 1H NMR (400 MHz, CDCl3) δ 7.80 (d, J = 9.1 Hz, 1H), 7.19−7.07 (m, 3H), 7.05−7.00 (m, 2H), 6.98−6.89 (m, 2H), 4294

DOI: 10.1021/acs.joc.7b00280 J. Org. Chem. 2017, 82, 4289−4296

Article

The Journal of Organic Chemistry Synthesis of d-4b. To a solution of t-BuOK (56.5 mg, 0.5 mmol) in DMSO-d6 (5 mL) was added 2-methylquinoline (1a, 0.7 mL, 5 mmol). The reaction mixture was then stirred at 80 °C under an argon atmosphere for 8 h. After the reaction mixture was cooled to room temperature, the water (5 mL) was added and followed by extraction with ethyl acetate (5 mL × 3). The combined organic layer was dried over anhydrous Na2SO4 and concentrated under vacuum. The crude product was purified by column chromatography on silica gel (300− 400 mesh) to afford d3-1a as a yellow oil. 2-(Methyl-d3)quinoline (d31a):26 light yellow oil; 1H NMR (400 MHz, CDCl3) δ 7.97 (d, J = 8.5 Hz, 1H), 7.91−7.84 (m, 1H), 7.63 (t, J = 7.7 Hz, 1H), 7.57 (ddd, J = 8.3, 6.9, 1.3 Hz, 1H), 7.35 (dt, J = 7.9, 3.8 Hz, 1H), 7.15−7.07 (m, 1H), 2.61 (dd, J = 4.1, 2.0 Hz, 0.13H) ppm; 13C NMR (100 MHz, CDCl3) δ 158.8, 147.7, 136.1, 129.3, 128.4, 127.4, 126.4, 125.6, 121.9, 24.6, 24.4, 24.1 ppm; HRMS (m/z) (ESI) calcd for C10H7D3N 147.1002 [M + H+], found 147.0998. The d3-1a (0.5 mmol) and aldehydes (0.6 mmol) were dissolved with 1 mL of PhCl in 25 mL of tube sealing. The reaction mixture was stirred at 140 °C overnight. Subsequently, the diethyl but-2-ynedioate (1 mmol) was added. The reaction mixture was stirred at 120 °C for another 8 h. Then, the PhCl was removed under vacuum. The crude product was purified by column chromatography on silica gel (300− 400 mesh) to afford desired product d-4b in 83% yield. The products were further identified by 1H NMR and HRMS. Dimethyl 3-(Phenylmethyl-d)pyrrolo[1,2-a]quinoline-1,2-dicarboxylate (d-4b). White solid; mp 86−87 °C; 1H NMR (400 MHz, CDCl3) δ 7.76 (d, J = 8.5 Hz, 1H), 7.58 (d, J = 7.7 Hz, 1H), 7.42 (ddd, J = 8.7, 7.3, 1.6 Hz, 1H), 7.35−7.31 (m, 1H), 7.22 (d, J = 10.1 Hz, 1H), 7.20−7.08 (m, 5H), 7.05−7.01 (m, 1H), 4.30 (s, 1H), 4.03 (s, 3H), 3.78 (s, 3H) ppm; HRMS (m/z) (ESI) calcd for C23H18DNO4 375.1455 [M + H+], found 375.1442.

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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.7b00280. Crystallographic file for 4f (CIF) Crystallographic file for 4o (CIF) X-ray crystal structures and copies of 1H and 13C NMR spectra of all compounds (PDF)

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AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected]. *E-mail: [email protected]. Phone: +86-773-5893619. Fax: +86-773-5895132. ORCID

Ying-ming Pan: 0000-0002-3625-7647 Author Contributions §

F.-s.W. and H.-y.Z. contributed equally to this work.

Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We would like to thank the National Natural Science Foundation of China (21362002 and 81260472), Guangxi Natural Science Foundation of China (2014GXNSFDA118007 and 2016GXNSFEA380001), and Project of Guangxi Department of Education (KY2014037).

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REFERENCES

(1) (a) Hitora, Y.; Takada, K.; Ise, Y.; Okada, S.; Matsunaga, S. J. Nat. Prod. 2016, 79, 2973−2976. (b) Fan, H.; Peng, J.-G.; Hamann, M. T.; Hu, J.-F. Chem. Rev. 2008, 108, 264−287. 4295

DOI: 10.1021/acs.joc.7b00280 J. Org. Chem. 2017, 82, 4289−4296

Article

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DOI: 10.1021/acs.joc.7b00280 J. Org. Chem. 2017, 82, 4289−4296